Methods of prognosis and treatment of patients suffering from MYC-high tumors

Abstract

The MYC and NMYC transcription factors (TFs) play a key role in cell proliferation and are overexpressed in most cancer cells. However, in normal cells their overexpression triggers safeguard mechanisms promoting cell death and cellular senescence, which are bypassed in cancer cells. Here, the inventors reveal that in normal cells MYC binds to the Inositol 1,4,5-Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER-mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC / ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and / or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1, via an BCL2-BH4 domain inhibitor induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Thus, the present invention relates to a method for treating MYChigh cancer, and in particular NMYC--amplified neuroblastoma in a subject by administering an BCL2-BH4 domain inhibitor.

Description

[0001]METHODS OF PROGNOSIS AND TREATMENT OF PATIENTS SUFFERING FROM MYC-HIGH TUMORS FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular oncology. BACKGROUND OF THE INVENTION: MYC is a widely expressed transcription factor (TF) that controls the expression of a large panel of target genes regulating multiple pathophysiological processes, including metabolism, proliferation, cell death, cellular senescence, cancer or aging1–3. The MYC TF is required for cell proliferation and exerts its pro-proliferative activity by inducing the transcription of genes encoding positive regulators of cell cycle, such as cyclins, cyclin- dependent kinases and E2F TFs4. Owing to the role of MYC in promoting cell proliferation, its gain-of-function is observed in 70% of cancers, where it acts as a critical driver of cancer formation and progression and can be a therapeutic target1,5. Nevertheless, pathogenic activation of MYC in normal cells initially leads to the activation of safeguard mechanisms, mainly cell death and cellular senescence, that counteract its pro-oncogenic effects. MYC promotes these cytotoxic and cytostatic effects by directly inducing the transcription of pro- apoptotic factors of the BCL2 family, such as BIM, or by inducing the transcription of p14ARF, p15INK4Band / or DNA damage, which leads to the activation of p53. Hence, in order to develop, cancer cells must inhibit or circumvent these regulators of apoptosis and senescence6,7. MYC belongs to a family of TFs including NMYC which is primarily expressed in the nervous system during development. MYC and NMYC are considered functionally equivalent, albeit they promote different types of tumors due to their distinct expression profiles8–11. Although several targets and downstream effector pathways are documented, the mechanisms by which MYC TFs induce their effects are only partially understood. Ca2+levels as well as its dynamics within the cell participate in crucial cellular processes that include cell proliferation, metabolism, cellular senescence and cell death12–18, reminiscent of the broad spectrum of effects induced by MYC1,3,19. Although Ca2+is required for cell viability and functions, cells tightly regulate Ca2+levels and distribution, given that high levels in some organelles are toxic. Indeed, cells maintain low Ca2+concentrations in the cytoplasm, whereas some organelles, such as the endoplasmic reticulum (ER), store it efficiently and release it upon stimulation. ER-mitochondria Ca2+transfer has been described in the process of cell death, during which mitochondrial Ca2+accumulation induces mitochondrial permeabilization and fatal cytochrome c release17,20, and was more recently shown to lead to cellular senescence in normal cells14,15,18,21–23. Inositol 1,4,5-Trisphosphate Receptor ITPRs or IP3Rs, a family of 3 members, are channels ensuring release of Ca2+from the ER and thus contributing to the accumulation of Ca2+in the mitochondria, thereby regulating cell death and cellular senescence18,23,24. Here, we reveal that in normal cells MYC directly binds to the ITPR1 gene and upregulates its expression, thus promoting ER-mitochondrial Ca2+transfer, cell death and cellular senescence. In cancer cells, the function of ITPR1 is largely lost, either owing to a decrease in its expression, or to an increase in the expression of BCL2, encoding an inhibitor of this channel. Strikingly, in NMYC-amplified neuroblastomas, NMYC controls the expression of ITPR1. In this context, NMYC / ITPR1 / mitochondrial Ca2+-dependent cell death can be restored by blocking the inhibitory effect of BCL2 on ITPR1, suggesting a new vulnerability of these high-risk cancers and more globally to tumors showing gain-of-function activity of MYC or MYCN and ITPR1 / BCL2 expression. SUMMARY OF THE INVENTION: The present invention is defined by the claims. The present invention relates to an in vitro method for predicting the survival time of a patient suffering from myc proto-oncogene proteins (MYC)hightumor comprising determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient, wherein the levels of ITPR1 positively correlate with a poor prognosis of survival. In another aspect, the invention relates to a method for treating NMYC-amplified cancer in a subject in need thereof comprising administering a therapeutically effective amount of a BCL2-BH4 domain inhibitor. DETAILED DESCRIPTION OF THE INVENTION: The inventors demontrated that in normal cells MYC binds to the Inositol 1,4,5- Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER- mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC / ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and / or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, the inventors show that in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1 induces mitochondrial Ca2+accumulation and cell death, and decreases tumor size. Collectively these data highlight a new function of MYC factors by controlling Ca2+signaling, which could constitute an unsuspected vulnerability for some cancer cells, including high-risk MYCN- amplified neuroblastoma cells. Methods for predicting the survival time Accordingly, in a first aspect, the invention relates to an in vitro method for classifying and / or stratifying a MYChightumors in a patient comprising the steps of i) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient, ii) comparing the level determined at step i) with a predetermined reference value and iii) concluding that the patient has a ITPR1high- MYChightumor when each levels determined at step i) are higher than their predetermined reference value. In particular embodiment, it can be concluded that the patient has a ITPR1low- MYChigh- tumor when the levels determined at step i) are lower than their predetermined reference value. In particular embodiment, the level of BCL2 can further be determined in step i), and wherein it is concluding in step iii) that the patient has a ITPR1high- BCL2highMYChightumor when each level determined at step i) are higher than their predetermined reference value. In some embodiments, the patient having a ITPR1high-MYChightumor exhibits a higher- risk MYChightumor, i.e a more severe form of tumor with a poorest prognostic of survival. In some embodiments, the patient having a ITPR1high-BCL2high-MYChightumor exhibits a higher-risk MYChightumor, i.e a more severe form of tumor with a poorest prognostic of survival. Thus, the invention relates to an in vitro method for predicting the survival time of a patient suffering from MYChightumor comprising determining the level of Inositol 1,4,5- trisphosphate receptor type 1 (ITPR1) from a sample of the patient, wherein the levels of ITPR1 positively correlate with a poor prognosis of survival. In other words, the invention relates to an in vitro method for assessing a MYChightumors patient’s risk of having a poor prognostic of survival comprising determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient, wherein the levels of ITPR1 positively correlate with a poor prognosis of survival. Typically, high risk neuroblastoma are generally amplified for MYCN and MYCN amplification indicates high risk of having a poor prognostic of survival. Typically, in MYChightumors, high level of ITPR1, and especially high level of ITPR1 and BCL2 indicates that the subject is at higher risk of having a poor prognostic of survival. Typically, in MYChightumors, low level of ITPR1, and more particularly low level of ITPR1 and BCL2, indicates that the subject is at high risk of having a good prognostic of survival. Thus, in a first aspect, the invention relates to an in vitro method for assessing a cancer patient’s risk of having a poor prognostic of survival in MYChightumors comprising i) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient, ii) comparing said levels determined at step i) with a predetermined reference value and iii) concluding that the patient subject is at high risk of having a poor prognostic when said level determined at step i) are higher than its predetermined reference value. In particular embodiment, it is concluded that the patient is at high risk of having a better prognostic when said level determined at step i) are lower than their predetermined reference value. In particular embodiment, the invention relates to an in vitro method for assessing a cancer patient’s risk of having a poor prognostic of survival in MYChightumors comprising i) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) and BCL2 from a sample of the patient, ii) comparing each levels determined at step i) with a predetermined reference value and iii) concluding that the patient subject is at high risk of having a poor prognostic when each levels determined at step i) are higher than their predetermined reference value. Typically a low level of ITPR1 and BCL2 indicates that the subject is at high risk of having a good prognostic of survival. As used herein, the term “subject” or “patient” refers to any mammal, such as a rodent, a feline, a canine, and a primate. Notably, in the present invention, the subject is a human. More particularly, the subject according to the invention has or is susceptible to have MYChighcancer. More particularly the subject has or is susceptible to have haematopoietic or lymphoid MYChigh cancer such as leukemia, lymphoma, and myeloma. More particularly the subject has or is susceptible to have MYCN-amplified neuroblastoma. As used herein, the term “sample” refers to any sample obtained from the subject for the purpose of performing the method of the present invention. In some embodiments, the sample is a bodily fluid (e.g. a blood sample) or a tissue. In some embodiments, the sample is a tissue sample. The term “tissue sample” includes sections of tissues such as biopsy or autopsy samples, fixed or and frozen sections taken for histological purposes. As used herein, the term “blood sample” means any blood sample derived from the subject. Collections of blood samples can be performed by methods well known to those skilled in the art. In some embodiments, the blood sample is a serum or plasma sample. In a particular embodiment, the sample has been previously obtained from the subject. As used herein, the term “cancer” or “tumor” refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. This term refers to any type of malignancy (primary or metastases) in any type of subject. It may refer to solid tumor as well as hematopoietic tumor. In a particular embodiment, the cancer is haematopoietic or lymphoid cancer such as leukemia, lymphoma, and myeloma. In a particular embodiment, the cancer is kidney cancer or lung cancer. In a particular embodiment, the cancer is selected from the group consisting of neuroblastoma, medulloblastoma, rhabdomyosarcoma, hodgkin lymphoma, mantle cell lymphoma, B-cell prolymphocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, B‐lymphoblastic leukemia / lymphoma, T‐lymphoblastic leukemia / lymphoma, diffuse large B‐cell lymphoma, mycosis fungoides, plasma cell myeloma, myelodysplastic syndromes, acute monoblastic / monocytic leukemia, T‐cell leukemia / lymphoma, chronic eosinophilic leukemia, acute monoblastic / monocytic leukemia, chronic lymphocytic leukemia / small lymphocytic, renal cell carcinoma and non-small cell lung cancer. In preferred embodiment, the tumor is neuroblastoma. As used herein, the term “MYChighcancer” or “MYChightumor” has its general meaning in the art and refers to tumor exhibiting an overexpression of MYC and / or an increased MYC biological activity. MYC expression is highly regulated, such that its level of expression is tightly controlled by a number of mechanisms involving many transcriptional regulatory motifs found within its proximal promoter region. Myc proteins stability can also be regulated by a number of mechanisms, such as via the Ras / Raf / MAPK pathway. MYChightumor includes but are not limited to tumors exhibiting gain-of-function of MYC transcription factors, MYC- amplified tumors, tumors associated with enhanced MYC stabilization and / or translocation. When the tumor is a neuroblastoma, the neuroblastoma is defined as MYChighwhen MYC and especially MYCN is amplified. In some embodiment the MYChighcancer is a MYCNhightumor or a C-MYChightumor. As used herein, the term “myc proto-oncogene proteins” or “MYC”, also known as bHLH transcription factors, refers to a family of regulator and proto-oncogene transcription factors. The Myc family consists of three related human genes: c-myc (MYC or C-MYC), l- myc (MYCL), and n-myc (MYCN). Myc proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). As used herein, the term “N-myc proto-oncogene protein” or “NMYC” or “MYCN”, also known as basic helix-loop-helix protein 37 (bHLHe37) refers to a protein located in the cell nucleus which is critical for normal brain development. Amplification and overexpression of N-Myc can lead to tumorigenesis. Its Entrez reference is 4613 and its UniProt reference is P04198. In some embodiment the MYChighcancer is a MYC-amplified cancer As used herein, the term “MYC-amplified cancer” or “MYC-amplified tumor” has its general meaning in the art and refers to tumor having an increased number of copies of the MYC gene in DNA tumor. Tumor exhibiting a MYC amplification can be defined as exhibiting at least 2 or more additional copy of MYC in DNA tumor or defined as 2-fold increase in MYC gene copy number. Techniques to detect a MYC-amplified tumor are well known in the art and are well utilized in clinical routine. Example of techniques include but are not limited to fluorescence in situ hybridization as described in Motaparthi K. et al, MYC gene amplification by fluorescence in situ hybridization and MYC protein expression by immunohistochemistry in the diagnosis of cutaneous angiosarcoma: Systematic review and appropriate use criteria. J Cutan Pathol.2021. In particular embodiment, the MYC-amplified tumor is a MYCN-amplified tumor or a C-MYC-amplified tumor. As used herein, the term “MYCN-amplified cancer” or “MYCN-amplified tumor” has its general meaning in the art and refers to tumor having an increased number of copies of the NMYC gene in DNA tumor. In some embodiment, the MYCN-amplified tumor is a MYCN-amplified neuroblastoma. As used herein, the term “inositol 1,4,5-trisphosphate recep tor type 1” or “ITPR1”, or IP3R, refers to a receptor which mediates calcium release from the endoplasmic reticulum. ITPR1 thus contributes to the accumulation of Ca2+in the mitochondria, thereby regulating cell death and cellular senescence Its Entrez reference is 3708 and its UniProt reference is Q14643. In particular embodiment, the level of BCL2 can further be determined in step i), and wherein each level of ITPR1 and BCL2 positively correlate with a poor prognosis of survival. As used herein, the term “BCL2” also known as “B-cell CLL / lymphoma 2” or “apoptosis regulator” refers to a regulator protein which blocks the apoptotic death of some cells such as lymphocytes. BCL2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The Bcl-2 family is characterized by specific regions of homology termed Bcl-2 homology (BH1, BH2, BH3, BH4) domains, which are critical to the function of these proteins, including their impact on cell survival and their ability to interact with other family members and regulatory proteins. BH1 and BH2 domains are required for the interaction with BAX and for anti-apoptotic activity. The BH4 motif is required for anti-apoptotic activity and for interaction with RAF1 and EGLN3. The loop between motifs BH4 and BH3 is required for the interaction with NLRP1. The BH3 domain is required for interaction with SEPTIN4 isoform ARTS and thereby for XIAP-mediated ubiquitination and subsequent induction of apoptosis. Its Entrez reference is 596 and its UniProt reference is P10415.The amino acid sequence of BCL2 is represented by SEQ IN NO:1. SEQ ID NO:1 (UNIPROT ref. P10415; BH4 domain is underlined): MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPAASRDPV ARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLHLTPFTARGRFAT VVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEYLNRHLHTWIQDNGGWDAF VELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK As used herein, the term "risk", in the context of the present invention, relates to the probability that an event will occur over a specific period and can mean a subject's "absolute" risk or "relative" risk. Absolute risk can be measured with reference to either actual observation post-measurement for the relevant time cohort or with reference to index values developed from statistically valid historical cohorts that have been followed for the relevant time period. Relative risk refers to the ratio of a subject's absolute risks compared to the absolute risks of low-risk cohorts or an average population risk, which can vary by how clinical risk factors are assessed. Odds ratios, the proportion of positive events to negative events for a given test result, are also commonly used (odds are according to the formula p / (l-p) where p is the probability of an event and (1- p) is the probability of no event) to no- conversion. "Risk evaluation," or "evaluation of risk" in the context of the present invention, encompasses predicting the probability, odds, or likelihood that an event or disease state may occur, the rate of occurrence of the event or conversion from one disease state to another. Risk evaluation can also comprise the prediction of future clinical parameters, traditional laboratory risk factor values, or other indices of relapse, either in absolute or relative terms in reference to a previously measured population. The methods of the present invention may be used to make continuous or categorical measurements of the risk of conversion, thus diagnosing and defining the risk spectrum of a category of subjects defined as being at risk of conversion. In the categorical scenario, the invention can be used to discriminate between normal and other subject cohorts at higher risk. In some embodiments, the present invention may be used so as to discriminate those at risk from normal. As used herein, the term “high” refers to a measure greater than normal, greater than a standard such as a predetermined reference value or a subgroup measure, or relatively greater than another subgroup measure. For example, a high level of a protein of interest (i.e ITPR1 and / or BCL2) refers to a level of the protein of interest that is greater than a normal level. A normal level may be determined according to any method available to one skilled in the art. A high level of a protein of interest (i.e ITPR1 and / or BCL2) may also refer to a level that is equal to or greater than a predetermined reference value, such as a predetermined cutoff. A high level of a protein of interest (i.e ITPR1 and / or BCL2) may also refer to a level of a protein of interest (i.e ITPR1 and / or BCL2) wherein a high protein of interest (i.e ITPR1 and / or BCL2) subgroup has relatively greater levels of protein of interest (i.e ITPR1 and / or BCL2) than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a subgroup whose measure is high (i.e., higher than the median) and another subgroup whose measure is low. In some cases, a “high” level may comprise a range of levels that is very high and a range of levels that is “moderately high,” where moderately high is a level that is greater than normal but less than “very high”. As used herein, the term “low” refers to a level that is less than normal or less than a standard, such as a predetermined reference value or a subgroup measure that is relatively less than another subgroup level. For example, a low level of a protein of interest (i.e ITPR1 and / or BCL2) means a level of the protein of interest (i.e ITPR1 and / or BCL2) that is less than a normal level of in a particular set of samples of patients. A normal level of a protein of interest (i.e ITPR1 and / or BCL2) measure may be determined according to any method available to one skilled in the art. A low level of a protein of interest (i.e ITPR1 and / or BCL2) may also mean a level that is less than a predetermined reference value, such as a predetermined cutoff. A low level of protein of interest (i.e ITPR1 and / or BCL2) may also indicate a level wherein a low level of protein of interest (i.e ITPR1 and / or BCL2) subgroup is relatively lower than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a group whose measure is low (i.e., less than the median) with respect to another group whose measure is high (i.e., greater than the median). The detection and quantification of ITPR1 and / or BCL2 in the MYChightumor patient’s sample can be detected by any method known in the art. As used herein, the term "expression level" refers, e.g., to a determined level of expression of gene of interest or protein of interest (i.e ITPR1 and / or BCL2). The expression level of expression indicates the amount of expression product in a sample. The expression product of a gene of interest can be the nucleic acid of interest itself, a nucleic acid transcribed or derived therefrom, or a polypeptide or protein derived therefrom. Measuring the expression level of ITPR1 and / or BCL2 can be done by measuring the gene expression level of these genes and can be performed by a variety of techniques well known in the art. Typically, the expression level of a gene may be determined by determining the quantity of mRNA. Methods for determining the quantity of mRNA are well known in the art. For example, the nucleic acid contained in the samples (e.g., cell or tissue prepared from the patient) is first extracted according to standard methods, for example using lytic enzymes or chemical solutions or extracted by nucleic-acid-binding resins following the manufacturer's instructions. The extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and / or amplification (e.g., RT-PCR). Other methods of Amplification include ligase chain reaction (LCR), transcription- mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence-based amplification (NASBA). Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. Typically, the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes. In various applications, such as in situ hybridization procedures, a nucleic acid probe includes a label (e.g., a detectable label). A “detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample. Thus, a labelled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labelled uniquely specific nucleic acid molecule is bound or hybridized) in a sample. A label associated with one or more nucleic acid molecules (such as a probe generated by the disclosed methods) can be detected either directly or indirectly. A label can be detected by any known or yet to be discovered mechanism including absorption, emission and / or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons). Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colourless substance into a coloured substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials. Particular examples of detectable labels include fluorescent molecules (or fluorochromes). Numerous fluorochromes are known to those of skill in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies). Examples of particular fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U.S. Pat. No.5,866, 366 to Nazarenko et al., such as 4-acetamido-4'-isothiocyanatostilbene-2,2' disulfonic acid, acridine and derivatives such as acridine and acridine isothiocyanate, 5-(2'-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS), 4-amino -N- [3 vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS), N-(4-anilino-1- naphthyl)maleimide, antl1ranilamide, Brilliant Yellow, coumarin and derivatives such as coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4- trifluoromethylcouluarin (Coumarin 151); cyanosine; 4',6-diarninidino-2-phenylindole (DAPI); 5',5"dibromopyrogallol-sulfonephthalein (Bromopyrogallol Red); 7 -diethylamino -3 - (4'-isothiocyanatophenyl)-4-methylcoumarin; diethylenetriamine pentaacetate; 4,4'- diisothiocyanatodihydro-stilbene-2,2'-disulfonic acid; 4,4'-diisothiocyanatostilbene-2,2'- disulfor1ic acid; 5-[dimethylamino] naphthalene-1-sulfonyl chloride (DNS, dansyl chloride); 4-(4'-dimethylaminophenylazo)benzoic acid (DABCYL); 4-dimethylaminophenylazophenyl- 4'-isothiocyanate (DABITC); eosin and derivatives such as eosin and eosin isothiocyanate; erythrosin and derivatives such as erythrosin B and erythrosin isothiocyanate; ethidium; fluorescein and derivatives such as 5-carboxyfluorescein (FAM), 5-(4,6dicl1lorotriazin-2- yDarninofluorescein (DTAF), 2'7'dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), fluorescein, fluorescein isothiocyanate (FITC), and QFITC Q(RITC); 2',7'-difluorofluorescein (OREGON GREEN®); fluorescamine; IR144; IR1446; Malachite Green isothiocyanate; 4- methylumbelliferone; ortho cresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B- phycoerythrin; o-phthaldialdehyde; pyrene and derivatives such as pyrene, pyrene butyrate and succinimidyl 1-pyrene butyrate; Reactive Red 4 (Cibacron Brilliant Red 3B-A); rhodamine and derivatives such as 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride, rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, rhodamine green, sulforhodamine B, sulforhodamine 101 and sulfonyl chloride derivative of sulforhodamine 101 (Texas Red); N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA); tetramethyl rhodamine; tetramethyl rhodamine isothiocyanate (TRITC); riboflavin; rosolic acid and terbium chelate derivatives. Other suitable fluorophores include thiol-reactive europium chelates which emit at approximately 617 mn (Heyduk and Heyduk, Analyt. Biochem.248:216-27, 1997; J. Biol. Chem.274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphthofluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof. Other fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrrometheneboron difluoride dyes, for example as described in U.S. Pat. Nos. 4,774,339, 5,187,288, 5,248,782, 5,274,113, 5,338,854, 5,451,663 and 5,433,896), Cascade Blue (an amine reactive derivative of the sulfonated pyrene described in U.S. Pat. No.5,132,432) and Marina Blue (U.S. Pat. No. 5,830,912). In addition to the fluorochromes described above, a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOTTM (obtained, for example, from Life Technologies (QuantumDot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat. Nos.6,815,064; 6,682,596; and 6,649, 138). Semiconductor nanocrystals are microscopic particles having size-dependent optical and / or electrical properties. When semiconductor nanocrystals are illuminated with a primary energy source, a secondary emission of energy occurs of a frequency that corresponds to the handgap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence. Semiconductor nanocrystals with different spectral characteristics are described in e.g., U.S. Pat. No. 6,602,671. Semiconductor nanocrystals that can he coupled to a variety of biological molecules (including dNTPs and / or nucleic acids) or substrates by techniques described in, for example, Bruchez et al., Science 281 :20132016, 1998; Chan et al., Science 281:2016-2018, 1998; and U.S. Pat. No. 6,274,323. Formation of semiconductor nanocrystals of various compositions are disclosed in, e.g., U.S. Pat. Nos. 6,927, 069; 6,914,256; 6,855,202; 6,709,929; 6,689,338; 6,500,622; 6,306,736; 6,225,198; 6,207,392; 6,114,038; 6,048,616; 5,990,479; 5,690,807; 5,571,018; 5,505,928; 5,262,357 and in U.S. Patent Puhlication No. 2003 / 0165951 as well as PCT Puhlication No. 99 / 26299 (puhlished May 27, 1999). Separate populations of semiconductor nanocrystals can he produced that are identifiable based on their different spectral characteristics. For example, semiconductor nanocrystals can he produced that emit light of different colors hased on their composition, size or size and composition. For example, quantum dots that emit light at different wavelengths based on size (565 mn, 655 mn, 705 mn, or 800 mn emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlshad, Calif.). Additional labels include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes. Detectable labels that can he used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase. Alternatively, an enzyme can he used in a metallographic detection scheme. For example, silver in situ hyhridization (SISH) procedures involve metallographic detection schemes for identification and localization of a hybridized genomic target nucleic acid sequence. Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate. (See, for example, U.S. Patent Application Puhlication No.2005 / 0100976, PCT Publication No. 2005 / 003777 and U.S. Patent Application Publication No.2004 / 0265922). Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate. (See, for example, U.S. Pat. No.6,670,113). Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH). In situ hybridization (ISH) involves contacting a sample containing target nucleic acid sequence (e.g., genomic target nucleic acid sequence) in the context of a metaphase or interphase chromosome preparation (such as a cell or tissue sample mounted on a slide) with a labeled probe specifically hybridizable or specific for the target nucleic acid sequence (e.g., genomic target nucleic acid sequence). The slides are optionally pretreated, e.g., to remove paraffin or other materials that can interfere with uniform hybridization. The sample and the probe are both treated, for example by heating to denature the double stranded nucleic acids. The probe (formulated in a suitable hybridization buffer) and the sample are combined, under conditions and for sufficient time to permit hybridization to occur (typically to reach equilibrium). The chromosome preparation is washed to remove excess probe, and detection of specific labeling of the chromosome target is performed using standard techniques. For example, a biotinylated probe can be detected using fluorescein-labeled avidin or avidin-alkaline phosphatase. For fluorochrome detection, the fluorochrome can be detected directly, or the samples can be incubated, for example, with fluorescein isothiocyanate (FITC)- conjugated avidin. Amplification of the FITC signal can be effected, if necessary, by incubation with biotin-conjugated goat antiavidin antibodies, washing and a second incubation with FITC- conjugated avidin. For detection by enzyme activity, samples can be incubated, for example, with streptavidin, washed, incubated with biotin-conjugated alkaline phosphatase, washed again and pre-equilibrated (e.g., in alkaline phosphatase (AP) buffer). For a general description of in situ hybridization procedures, see, e.g., U.S. Pat. No.4,888,278. Numerous procedures for FISH, CISH, and SISH are known in the art. For example, procedures for performing FISH are described in U.S. Pat. Nos. 5,447,841; 5,472,842; and 5,427,932; and for example, in Pir1kel et al., Proc. Natl. Acad. Sci.83:2934-2938, 1986; Pinkel et al., Proc. Natl. Acad. Sci. 85:9138-9142, 1988; and Lichter et al., Proc. Natl. Acad. Sci. 85:9664-9668, 1988. CISH is described in, e.g., Tanner et al., Am..1. Pathol.157:1467-1472, 2000 and U.S. Pat. No.6,942,970. Additional detection methods are provided in U.S. Pat. No. 6,280,929. Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties. As discussed above probes labeled with fluorophores (including fluorescent dyes and QUANTUM DOTS®) can be directly optically detected when performing FISH. Alternatively, the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety. Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand. The detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore. In other examples, the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH). As indicated above, the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos.2006 / 0246524; 2006 / 0246523, and 2007 / 0117153. It will be appreciated by those of skill in the art that by appropriately selecting labelled probe-specific binding agent pairs, multiplex detection schemes can he produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample). For example, a first probe that corresponds to a first target sequence can he labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP. Following exposure of the sample to the probes, the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn) and a second specific binding agent (in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 mn). Additional probes / binding agent pairs can he added to the multiplex detection scheme using other spectrally distinct fluorophores. Numerous variations of direct, and indirect (one step, two step or more) can he envisioned, all of which are suitable in the context of the disclosed probes and assays. Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500. Primers typically are shorter single-stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified. The probes and primers are “specific” to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC. SCC is a 0.15 M NaCl, 0.015 M Na-citrate). The nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit. Such a kit includes consensus primers and molecular probes. A preferred kit also includes the components necessary to determine if amplification has occurred. The kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences. In a particular embodiment, the methods of the invention comprise the steps of providing total RNAs extracted from cumulus cells and subjecting the RNAs to amplification and hybridization to specific probes, more particularly by means of a quantitative or semi- quantitative RT-PCR. In another preferred embodiment, the expression level is determined by DNA chip analysis. Such DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere-sized bead. A microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose. Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs. To determine the expression level, a sample from a test subject, optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface. The labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling. Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210). In another embodiment, the expression level is determined by metabolic imaging (see for example Yamashita T et al., Hepatology 2014, 60:1674-1685 or Ueno A et al., Journal of hepatology 2014, 61:1080-1087). Expression level of a gene may be expressed as absolute expression level or normalized expression level. Typically, expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the response of antipsychotic treatment, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1, TFRC, GAPDH, TBP and ABL1. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources. Measuring the expression level of the proteins ITPR1 and / or BCL2 can be performed by a variety of techniques well known in the art. Typically protein expression level may be measured for example by capillary electrophoresis-mass spectroscopy technique (CE-MS), flow cytometry, mass cytometry or ELISA performed on the sample. In the present application, the “level of protein” or the “protein level expression” means the quantity or concentration of said protein. In still another embodiment, the “level of protein” means the quantitative measurement of the protein expression relative to a negative control. Such methods comprise contacting a sample with a binding partner capable of selectively interacting with proteins present in the sample. The binding partner is generally an antibody that may be polyclonal or monoclonal, preferably monoclonal. The presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays. Such assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; biotin / avidin type assays; radioimmunoassays; immunoelectrophoresis; immunoprecipitation, capillary electrophoresis- mass spectroscopy technique (CE-MS).etc. The reactions generally include revealing labels such as fluorescent, chemioluminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith. The aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound. Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like. More particularly, an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art. Particularly, a mass spectrometry-based quantification methods may be used. Mass spectrometry-based quantification methods may be performed using either labelled or unlabelled approaches [DeSouza and Siu, 2012]. Mass spectrometry-based quantification methods may be performed using chemical labeling, metabolic labeling or proteolytic labeling. Mass spectrometry-based quantification methods may be performed using mass spectrometry label free quantification, a quantification based on extracted ion chromatogram (EIC) and then profile alignment to determine differential level of polypeptides. Particularly, a mass spectrometry-based quantification method particularly useful can be the use of targeted mass spectrometry methods as selected reaction monitoring (SRM), multiple reaction monitoring (MRM), parallel reaction monitoring (PRM), data independent acquisition (DIA) and sequential window acquisition of all theoretical mass spectra (SWATH) [Moving target Zeliadt N 2014 The Scientist;Liebler Zimmerman Biochemistry 2013 targeted quantitation pf proteins by mass spectrometry; Gallien Domon 2015 Detection and quantification of proteins in clinical samples using high resolution mass spectrometry. Methods v81 p15-23 ; Sajic, Liu, Aebersold, 2015 Using data-independent, high-resolution mass spectrometry in protein biomarker research: perspectives and clinical applications. Proteomics Clin Appl v9 p 307-21]. Particularly, the mass spectrometry-based quantification method can be the mass cytometry also known as cytometry by time of flight (CYTOF) (Bandura DR, Analytical chemistry, 2009). Particularly, the mass spectrometry-based quantification is used to do peptide and / or protein profiling can be use with matrix-assisted laser desorption / ionisation time of flight (MALDI-TOF), surface-enhanced laser desorption / ionization time of flight (SELDI-TOF; CLINPROT) and MALDI Biotyper apparatus [Solassol, Jacot, Lhermitte, Boulle, Maudelonde, Mangé 2006 Clinical proteomics and mass spectrometry profiling for cancer detection. Journal: Expert Review of Proteomics V3, I3, p311-320 ; FDA K130831]. Methods of the invention may comprise a step consisting of comparing the proteins and fragments concentration in circulating cells with a control value. As used herein, "concentration of protein" refers to an amount or a concentration of a transcription product, for instance the proteins of the invention. Typically, a level of a protein can be expressed as nanograms per microgram of tissue or nanograms per milliliter of a culture medium, for example. Alternatively, relative units can be employed to describe a concentration. In a particular embodiment, "concentration of proteins" may refer to fragments of the proteins of the invention. The predictive method of the present invention is particularly suitable for predicting the duration of the overall survival (OS), progression-free survival (PFS) and / or the disease-free survival (DFS) of the cancer patient. Those of skill in the art will recognize that OS survival time is generally based on and expressed as the percentage of people who survive a certain type of cancer for a specific amount of time. Cancer statistics often use an overall five-year survival rate. In general, OS rates do not specify whether cancer survivors are still undergoing treatment at five years or if they've become cancer-free (achieved remission). DSF gives more specific information and is the number of people with a particular cancer who achieve remission. Also, progression-free survival (PFS) rates (the number of people who still have cancer, but their disease does not progress) includes people who may have had some success with treatment, but the cancer has not disappeared completely. Typically, the expression “short survival time” indicates that the patient will have a survival time that will be lower than the median (or mean) observed in the general population of patients suffering from said cancer. When the patient will have a short survival time, it is meant that the patient will have a “poor prognosis”. Inversely, the expression “long survival time” indicates that the patient will have a survival time that will be higher than the median (or mean) observed in the general population of patients suffering from said cancer. When the patient will have a long survival time, it is meant that the patient will have a “good prognosis”. In some embodiments, the “predetermined reference value” is relative to a number or value derived from population studies, including without limitation, patients of the same or similar age range, patients in the same or similar ethnic group, and patients having the same severity of cancer. Such predetermined reference values can be derived from statistical analyses and / or risk prediction data of populations obtained from mathematical algorithms and computed indices of the disease. Typically, the predetermined reference value is a threshold or cutoff value. Typically, a "threshold value" or "cutoff value" can be determined experimentally, empirically, or theoretically. A threshold value can also be arbitrarily selected based on the existing experimental and / or clinical conditions, as would be recognized by a person of ordinary skill in the art. For example, retrospective measurement in properly banked historical subject samples may be used in establishing the predetermined reference value. The threshold value has to be determined to obtain the optimal sensitivity and specificity according to the function of the test and the benefit / risk balance (clinical consequences of false positive and false negative). Typically, the optimal sensitivity and specificity (and the threshold value) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data. For example, after determining the level of ITPR1 and BCL2 in a group of reference, one can use algorithmic analysis to statistically treat the levels determined in samples to be tested and thus obtain a classification standard having significance for sample classification. The full name of the ROC curve is the receiver operator characteristic curve, also known as the receiver operation characteristic curve. It is mainly used for clinical and biochemical diagnostic tests. The ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1-specificity). It reveals the relationship between sensitivity and specificity with the image composition method. A series of different cutoff values (thresholds or critical values, boundary values between normal and abnormal diagnostic test results) are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate, and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis. On the ROC curve, the point closest to the far upper left of the coordinate diagram is a critical point with high sensitivity and specificity values. The AUC value of the ROC curve is between 1.0 and 0.5. When AUC>0.5, the diagnostic result improves as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate. When AUC is higher than 0.9, the accuracy is high. This algorithmic method is preferably done with a computer. Existing software or systems in the art may be used to draw the ROC curve, such as MedCalc 9.2.0.1 medical statistical software, SPSS 9.0, ROCPOWER.SAS, DESIGNROC.FOR, MULTIREADER POWER.SAS, CREATE-ROC.SAS, GB STAT VI0.0 (Dynamic Microsystems, Inc. Silver Spring, Md., USA), etc. In some embodiments, the predetermined reference value is typically determined by carrying out a method comprising the steps of: a) providing a collection of samples from patients suffering from MYChigh-amplified tumors; b) providing, for each sample provided at step a), information relating to the actual clinical outcome for the corresponding patient (i.e. the duration of the disease-free survival (DFS) and / or the overall survival (OS)); c) providing a serial of arbitrary quantification values; d) determining the level of the marker of interest (i.e. ITPR1 and / or BCL2) for each sample contained in the collection provided at step a); e) classifying said samples in two groups for one specific arbitrary quantification value provided at step c), respectively: (i) a first group comprising samples that exhibit a quantification value for level that is lower than the said arbitrary quantification value contained in the said serial of quantification values; (ii) a second group comprising samples that exhibit a quantification value for said level that is higher than the said arbitrary quantification value contained in the said serial of quantification values; whereby two groups of samples are obtained for the said specific quantification value, wherein the samples of each group are separately enumerated; f) calculating the statistical significance between (i) the quantification value obtained at step e) and (ii) the actual clinical outcome of the patients from which samples contained in the first and second groups defined at step f) derive; g) reiterating steps f) and g) until every arbitrary quantification value provided at step d) is tested; h) setting the said predetermined reference value as consisting of the arbitrary quantification value for which the highest statistical significance (most significant) has been calculated at step g). An additional object of the invention relates to an in vitro method for monitoring a MYChightumor in a patient comprising the steps of i) determining the level of Inositol 1,4,5- trisphosphate receptor type 1 (ITPR1) from a sample of the patient at a first specific time, ii) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient at a second specific time, iii) comparing said level determined at step i) with the level determined at step ii), and iv) concluding that the tumor has evolved in worse manner when the level determined at step ii) is higher than the level determined at step i). In particular embodiment, the level of BCL2 can further be determined in step i) and step ii), and wherein it is concluding that in step iv) that the tumor has evolved in worse manner when the levels of ITPR1 and BCL2 determined at step ii) is higher than the levels determined at step i) for each. An additional object of the invention relates to an in vitro method for monitoring the treatment of a MYChightumor in a patient comprising the steps of i) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient at a first specific time, ii) determining the level of Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) from a sample of the patient at a second specific time, iii) comparing the level determined at step i) with the level determined at step ii), and iv) concluding that the treatment is efficient when the level determined at step ii) is lower than the level determined at step i). In some embodiments, the first-time specific time where the level of ITPR1 is determined at step i) is before or at the beginning of said treatment. In particular embodiment, the level of BCL2 can further be determined in step i) and step ii), and wherein it is concluding that in step iv) that the treatment is efficient when the levels of ITPR1 and BCL2 determined at step ii) is higher than the levels determined at step i) for each. In some embodiments, the treatment refers to any suitable agent to treat MYChightumor. Anti-cancer therapy include but are not limited to radiation therapy, antibody therapy, immune checkpoint inhibitor, CAR Therapy, such as CAR T- , CAR M- or CAR NK-cell therapy, antibody-drug conjugates (ADC), BH3 mimetics or chemotherapy. Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As used herein, the term "chemotherapeutic agent" refers to chemical compounds that are effective in inhibiting tumor growth. Examples of chemotherapeutic agents include multkinase inhibitors such as sorafenib and sunitinib, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimus tine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idanrbicin, marcellomycin, mitomycins, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomgrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophospharnide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defo famine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pento statin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogennanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylarnine; trichothecenes (especially T-2 toxin, verracurin A, roridinA and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobromtol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisp latin and carbop latin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are antihormonal agents that act to regulate or inhibit honnone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. As used herein, the term “radiation therapy” has its general meaning in the art and refers the treatment of cancer with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated (the target tissue) by damaging their genetic material, making it impossible for these cells to continue to grow. One type of radiation therapy commonly used involves photons, e.g. X-rays. Depending on the amount of energy they possess, the rays can be used to destroy cancer cells on the surface of or deeper in the body. The higher the energy of the x-ray beam, the deeper the x-rays can go into the target tissue. Linear accelerators and betatrons produce x-rays of increasingly greater energy. The use of machines to focus radiation (such as x-rays) on a cancer site is called external beam radiation therapy. Gamma rays are another form of photons used in radiation therapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, and cobalt 60) release radiation as they decompose, or decay. In some embodiments, the radiation therapy is external radiation therapy. Examples of external radiation therapy include, but are not limited to, conventional external beam radiation therapy; three-dimensional conformal radiation therapy (3D-CRT), which delivers shaped beams to closely fit the shape of a tumor from different directions; intensity modulated radiation therapy (IMRT), e.g., helical tomotherapy, which shapes the radiation beams to closely fit the shape of a tumor and also alters the radiation dose according to the shape of the tumor; conformal proton beam radiation therapy; image-guided radiation therapy (IGRT), which combines scanning and radiation technologies to provide real time images of a tumor to guide the radiation treatment; intraoperative radiation therapy (IORT), which delivers radiation directly to a tumor during surgery; stereotactic radiosurgery, which delivers a large, precise radiation dose to a small tumor area in a single session; hyperfractionated radiation therapy, e.g., continuous hyperfractionated accelerated radiation therapy (CHART), in which more than one treatment (fraction) of radiation therapy are given to a subject per day; and hypofractionated radiation therapy, in which larger doses of radiation therapy per fraction is given but fewer fractions. As used herein, the term "immune checkpoint protein" has its general meaning in the art and refers to a molecule that is expressed by T lymphocytes in that either turn up a signal (stimulatory checkpoint molecules) or turn down a signal (inhibitory checkpoint molecules). Immune checkpoints are the regulators of the immune system. They are crucial for self- tolerance, which prevents the immune system from attacking cells indiscriminately. Immune checkpoints are targets for cancer immunotherapy due to their potential for use in multiple types of cancers. Typically, by using immune checkpoint inhibitors, the anti-tumoral response is reactivated by reactivation of cytotoxic T- lymphocytes. Immune checkpoint molecules are recognized in the art to constitute immune checkpoint pathways similar to the CTLA-4 and PD-1 dependent pathways (see e.g. Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al. , 2011. Nature 480:480- 489). Examples of stimulatory checkpoint molecules include CD27, CD28, CD40, CD122, CD137, OX40, GITR, and ICOS. Examples of inhibitory checkpoint molecules include A2AR, B7-H3, B7-H4, BTLA, CTLA-4, CD277, IDO, KIR, PD-1, LAG-3, TIM-3 and VISTA. The Adenosine A2A receptor (A2AR) is regarded as an important checkpoint in cancer therapy because adenosine in the immune microenvironment, leading to the activation of the A2a receptor, is negative immune feedback loop and the tumor microenvironment has relatively high concentrations of adenosine. B7-H3, also called CD276, was originally understood to be a co-stimulatory molecule but is now regarded as co-inhibitory. B7-H4, also called VTCN1, is expressed by tumor cells and tumor- associated macrophages and plays a role in tumour escape. B and T Lymphocyte Attenuator (BTLA) and also called CD272, has HVEM (Herpesvirus Entry Mediator) as its ligand. Surface expression of BTLA is gradually downregulated during differentiation of human CD8+ T cells from the naive to effector cell phenotype, however tumor-specific human CD8+ T cells express high levels of BTLA. CTLA-4, Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152. Expression of CTLA-4 on Treg cells serves to control T cell proliferation. IDO, Indoleamine 2,3-dioxygenase, is a tryptophan catabolic enzyme. A related immune-inhibitory enzymes. Another important molecule is TDO, tryptophan 2,3-dioxygenase. IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis. KIR, Killer-cell Immunoglobulin-like Receptor, is a receptor for MHC Class I molecules on Natural Killer cells. LAG3, Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs as well as direct effects on CD8+ T cells. PD-1, Programmed Death 1 (PD-1) receptor, has two ligands, PD-L1 and PD-L2. This checkpoint is the target of Merck & Co.'s melanoma drug Keytruda, which gained FDA approval in September 2014. An advantage of targeting PD-1 is that it can restore immune function in the tumor microenvironment. TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. TIM-3 acts as a negative regulator of Th1 / Tc1 function by triggering cell death upon interaction with its ligand, galectin-9. VISTA, Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on hematopoietic cells so that consistent expression of VISTA on leukocytes within tumors may allow VISTA blockade to be effective across a broad range of solid tumors. Tumor cells often take advantage of these checkpoints to escape detection by the immune system. Thus, inhibiting a checkpoint protein on the immune system may enhance the anti-tumor T-cell response. In particular embodiment, the patient identified as being at high risk of having a poorer prognostic of survival according to the method of the invention can be treated with an inhibitor of the BH4 domain of BCL2. The inventors neuroblastoma, blocking the interaction between BCL2 and ITPR1, by inhibiting the BH4 domain of BCL2, induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Accordingly, in a second aspect, the invention refers to a method for treating MYChightumor in a subject in need thereof comprising administering a therapeutically effective amount of an inhibitor of the BH4 domain of BCL2. In other words, the invention refers to an inhibitor of the BH4 domain of BCL2 for use for treating MYChightumor in a subject in need thereof. In particular embodiment, the MYChightumor is a C-MYChightumors or MYCNhightumors. In particular embodiment, the MYChightumor is a MYChightumor exhibiting high level of ITPR1, and more particularly high level of ITPR1 and BCL2. In particular embodiment, the MYChightumor is a MYC-amplified tumors or MYCN- amplified tumors. In particular embodiment, the MYChightumor is a MYCN-amplified neuroblastoma. In particular embodiment, the MYChightumor is a MYChighITPR1highclassified according to the method of the invention, and more particularly a MYChighITPR1highBCL2highclassified according to the method of the invention. In a particular embodiment, the tumor is selected from the group consisting of neuroblastoma, medulloblastoma and rhabdomyosarcoma, hodgkin lymphoma, mantle cell lymphoma, B-cell prolymphocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, B‐lymphoblastic leukemia / lymphoma, T‐lymphoblastic leukemia / lymphoma, diffuse large B‐cell lymphoma, mycosis fungoides, plasma cell myeloma, myelodysplastic syndromes, acute monoblastic / monocytic leukemia, T‐cell leukemia / lymphoma, chronic eosinophilic leukemia, acute monoblastic / monocytic leukemia, chronic lymphocytic leukemia / small lymphocytic, renal cell carcinoma and non-small cell lung cancer. In preferred embodiment, the tumor is neuroblastoma. In some embodiment, the tumor is resistant to inhibitor of BH3 mimetics. As used herein, the terms “treating” or “treatment” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). As used herein, the term “BH4 domain of BCL2 inhibitor” refers to any compound natural or not which is capable of neutralizing, blocking, inhibiting, abrogating, reducing, degrading or interfering with the activities of BH4 domain of BCL2, including reduction or blocking the interaction between said BH4 domain and ITPR1. BH4 domain of BCL2 inhibitors are well known in the art. The term encompasses any BH4 domain of BCL2 inhibitor that is currently known in the art or that will be identified in the future. The term also encompasses inhibitor of expression of BCL2-BH4 domain. The inhibition of the compounds may be determined using various methods well known in the art. By "biological activity" of BH4 domain of BCL2 is meant anti-apoptotic activity and interaction with ITPR1. Tests for determining the capacity of a compound to be an inhibitor of BH4 domain of BCL2 are well known to the person skilled in the art. In a preferred embodiment, the inhibitor specifically binds to BH4 domain of BCL2 in a sufficient manner to inhibit the biological activity of BH4 domain of BCL2. Binding to BH4 domain of BCL2 and inhibition of the biological activity of BH4 domain of BCL2 may be determined by any competing assays well known in the art. For example, the assay may consist in determining the ability of the agent to be tested as inhibitor of BH4 domain of BCL2 to bind to BH4 domain of BCL2. The binding ability is reflected by the Kd measurement. The term "KD", as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e. Kd / Ka) and is expressed as a molar concentration (M). KD values for binding biomolecules can be determined using methods well established in the art. In specific embodiments, an antagonist that "specifically binds to BH4 domain of BCL2 is intended to refer to an inhibitor that binds to human BH4 domain of BCL2 with a KD of 1μM or less, 100nM or less, 10nM or less, or 3nM or less. Then a competitive assay may be settled to determine the ability of the agent to inhibit biological activity of BH4 domain of BCL2. The functional assays may be envisaged such evaluating the ability to a) inhibit interaction between BCL2 and ITPR1 and / or b) reduced MYC-amplified and ITPR1hightumor growth, and especially MYCN-amplified and ITPR1highneuroblastoma growth (see example). By "interaction between BCL2 and an ITPR1" is meant the direct interaction between the antiapoptotic protein BCL2 with ITPR1 localized on the endoplasmic reticulum. The BCL2 interacting site of ITPR1 has been localized in the BH4 domain of BCL2. Tests for determining the capacity of a compound to be an inhibitor to BCL2 and ITPR1 interaction are well known in the art. Example includes cellular protein-protein interaction (PPI) assay such as using Förster resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) to identify compound that modulates the interaction, as described in Wade M, et al. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. In some embodiments, the inhibitor of BH4 domain of BCL2 can inhibit the ITPR1 inhibition by BCL2 and thus restore the ITPR1 activity, i.e restore apoptosis of cancer cell. In some embodiments, the inhibitor of BH4 domain of BCL2 is an inhibitor of the activity of BH4 domain of BCL2. Accordingly, the inhibitor of BH4 domain of BCL2 may be a molecule that binds to BH4 domain of BCL2 and is able to disrupt BCL2 / ITPR1 interaction selected from the group consisting of small molecule, antibodies, aptamers, and peptides / polypeptides. In one embodiment, the BCL2-BH4 domain activity inhibitor of the invention is an aptamer. “Aptamers” are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by EXponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990. The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S.D., 1999. Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996). Then after raising aptamers directed against BCL2-BH4 domain as above described, the skilled man in the art can easily select those inhibiting BCL2-BH4 domain. In another embodiment, the BCL2-BH4 domain activity inhibitor of the invention is an antibody (the term including “antibody portion”). In one embodiment of the antibodies or portions thereof described herein, the antibody is a monoclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a polyclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a humanized antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a chimeric antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a light chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a heavy chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fab portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a F(ab')2 portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fc portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fv portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a variable domain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises one or more CDR domains of the antibody. As used herein, "antibody" includes both naturally occurring and non-naturally occurring antibodies. Specifically, "antibody" includes polyclonal and monoclonal antibodies, and monovalent and divalent fragments thereof. Furthermore, "antibody" includes chimeric antibodies, wholly synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in man. Antibodies are prepared according to conventional methodology. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with antigenic forms of BCL2-BH4 domain. The animal may be administered a final "boost" of antigen within one week of sacrifice. It is often desirable to use an immunologic adjuvant during immunization. Suitable immunologic adjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG-containing immunostimulatory oligonucleotides. Other suitable adjuvants are well-known in the field. The animals may be immunized by subcutaneous, intraperitoneal, intramuscular, intravenous, intranasal or other routes. A given animal may be immunized with multiple forms of the antigen by multiple routes. Briefly, the antigen may be provided as synthetic peptides corresponding to antigenic regions of interest in BCL2-BH4 domain. Following the immunization regimen, lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma. Following fusion, cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods, as described (Coding, Monoclonal Antibodies: Principles and Practice: Production and Application of Monoclonal Antibodies in Cell Biology, Biochemistry and Immunology, 3rd edition, Academic Press, New York, 1996). Following culture of the hybridomas, cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen. Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non-denaturing ELISA, flow cytometry, and immunoprecipitation. Significantly, as is well-known in the art, only a small portion of an antibody molecule, the paratope, is involved in the binding of the antibody to its epitope (see, in general, Clark, W. R. (1986) The Experimental Foundations of Modern Immunology Wiley & Sons, Inc., New York; Roitt, I. (1991) Essential Immunology, 7th Ed., Blackwell Scientific Publications, Oxford). The Fc' and Fc regions, for example, are effectors of the complement cascade but are not involved in antigen binding. An antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region, designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody. Similarly, an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region, designated an Fab fragment, retains one of the antigen binding sites of an intact antibody molecule. Proceeding further, Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd. The Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation. Within the antigen-binding portion of an antibody, as is well-known in the art, there are complementarity determining regions (CDRs), which directly interact with the epitope of the antigen, and framework regions (FRs), which maintain the tertiary structure of the paratope (see, in general, Clark, 1986; Roitt, 1991). In both the heavy chain Fd fragment and the light chain of IgG immunoglobulins, there are four framework regions (FR1 through FR4) separated respectively by three complementarity determining regions (CDR1 through CDRS). The CDRs, and in particular the CDRS regions, and more particularly the heavy chain CDRS, are largely responsible for antibody specificity. It is now well-established in the art that the non CDR regions of a mammalian antibody may be replaced with similar regions of conspecific or heterospecific antibodies while retaining the epitopic specificity of the original antibody. This is most clearly manifested in the development and use of "humanized" antibodies in which non-human CDRs are covalently joined to human FR and / or Fc / pFc' regions to produce a functional antibody. This invention provides in certain embodiments compositions and methods that include humanized forms of antibodies. As used herein, "humanized" describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference. The above U.S. Pat. Nos. 5,585,089 and 5,693,761, and WO 90 / 07861 also propose four possible criteria which may used in designing the humanized antibodies. The first proposal was that for an acceptor, use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized, or use a consensus framework from many human antibodies. The second proposal was that if an amino acid in the framework of the human immunoglobulin is unusual and the donor amino acid at that position is typical for human sequences, then the donor amino acid rather than the acceptor may be selected. The third proposal was that in the positions immediately adjacent to the 3 CDRs in the humanized immunoglobulin chain, the donor amino acid rather than the acceptor amino acid may be selected. The fourth proposal was to use the donor amino acid reside at the framework positions at which the amino acid is predicted to have a side chain atom within 3A of the CDRs in a three dimensional model of the antibody and is predicted to be capable of interacting with the CDRs. The above methods are merely illustrative of some of the methods that one skilled in the art could employ to make humanized antibodies. One of ordinary skill in the art will be familiar with other methods for antibody humanization. In one embodiment of the humanized forms of the antibodies, some, most or all of the amino acids outside the CDR regions have been replaced with amino acids from human immunoglobulin molecules but where some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they would not abrogate the ability of the antibody to bind a given antigen. Suitable human immunoglobulin molecules would include IgGl, IgG2, IgG3, IgG4, IgA and IgM molecules. A "humanized" antibody retains a similar antigenic specificity as the original antibody. However, using certain methods of humanization, the affinity and / or specificity of binding of the antibody may be increased using methods of "directed evolution", as described by Wu et al., / . Mol. Biol.294:151, 1999, the contents of which are incorporated herein by reference. Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest. Following immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex / GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans. In vitro methods also exist for producing human antibodies. These include phage display technology (U.S. Pat. Nos.5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference. Thus, as will be apparent to one of ordinary skill in the art, the present invention also provides for F(ab') 2 Fab, Fv and Fd fragments; chimeric antibodies in which the Fc and / or FR and / or CDR1 and / or CDR2 and / or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric F(ab')2 fragment antibodies in which the FR and / or CDR1 and / or CDR2 and / or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric Fab fragment antibodies in which the FR and / or CDR1 and / or CDR2 and / or light chain CDR3 regions have been replaced by homologous human or non-human sequences; and chimeric Fd fragment antibodies in which the FR and / or CDR1 and / or CDR2 regions have been replaced by homologous human or non-human sequences. The present invention also includes so-called single chain antibodies. The various antibody molecules and fragments may derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4. I In another embodiment, the antibody according to the invention is a single domain antibody. The term “single domain antibody” (sdAb) or "VHH" refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such VHH are also called “nanobody®”. According to the invention, sdAb can particularly be llama sdAb. The term “VHH” refers to the single heavy chain having 3 complementarity determining regions (CDRs): CDR1, CDR2 and CDR3. The term “complementarity determining region” or “CDR” refers to the hypervariable amino acid sequences which define the binding affinity and specificity of the VHH. The VHH according to the invention can readily be prepared by an ordinarily skilled artisan using routine experimentation. The VHH variants and modified form thereof may be produced under any known technique in the art such as in-vitro maturation. VHHs or sdAbs are usually generated by PCR cloning of the V-domain repertoire from blood, lymph node, or spleen cDNA obtained from immunized animals into a phage display vector, such as pHEN2. Antigen-specific VHHs are commonly selected by panning phage libraries on immobilized antigen, e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells. However, such VHHs often show lower affinities for their antigen than VHHs derived from animals that have received several immunizations. The high affinity of VHHs from immune libraries is attributed to the natural selection of variant VHHs during clonal expansion of B-cells in the lymphoid organs of immunized animals. The affinity of VHHs from non-immune libraries can often be improved by mimicking this strategy in vitro, i.e., by site directed mutagenesis of the CDR regions and further rounds of panning on immobilized antigen under conditions of increased stringency (higher temperature, high or low salt concentration, high or low pH, and low antigen concentrations). VHHs derived from camelid are readily expressed in and purified from the E. coli periplasm at much higher levels than the corresponding domains of conventional antibodies. VHHs generally display high solubility and stability and can also be readily produced in yeast, plant, and mammalian cells. For example, the “Hamers patents” describe methods and techniques for generating VHH against any desired target (see for example US 5,800,988; US 5,874, 541 and US 6,015,695). The “Hamers patents” more particularly describe production of VHHs in bacterial hosts such as E. coli (see for example US 6,765,087) and in lower eukaryotic hosts such as moulds (for example Aspergillus or Trichoderma) or in yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia) (see for example US 6,838,254). In particular embodiment, the antibody is able to enter into cells, i.e pass through cellular or subcellular membranes in living cells It is well known by the skilled man in the art techniques to deliver therapeutics antibodies into specific cells, as described in Gaston, J., et al. Intracellular delivery of therapeutic antibodies into specific cells using antibody-peptide fusions. Sci Rep 9, 18688 (2019) or Muller, S., et al. (2005). TransMabs: cell-penetrating antibodies, the next generation. Expert Opinion on Biological Therapy, 5(2), 237–241. In one embodiment, the BCL2-BH4 domain inhibitor is a small organic molecule. As used herein, the term "small organic molecule" refers to a molecule of size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e.g.; proteins, nucleic acids, etc.); preferred small organic molecules range in size up to 2000 Da, and most preferably up to about 1000 Da. Small organic BCL2-BH4 domain inhibitors are well known in the art. Example of BCL2-BH4 domain inhibitors include but are not limited to SM396, SM216 and SM949 (as described in Kanakaveti V et al. Novel BH4-BCL-2 Domain Antagonists Induce BCL-2- Mediated Apoptosis in Triple-Negative Breast Cancer. Cancers (Basel).2022 Oct 2); CYD0281 (as decribed in Lin Y, et al. CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth. BMC Cancer.2023 May). In one embodiment, the BCL2-BH4 domain inhibitor is a peptide or a peptidometic. The term “peptidomimetic” refers to a small protein-like chain designed to mimic a peptide. Peptide BCL2-BH4 domain inhibitors are well known in the art. Example of BCL2- BH4 domain inhibitors include but are not limited to Bird2 (SEQ ID NO:2). SEQ ID NO:2 Bird2 RKKRRQRRRGGNVYTEIKCNSLLPLAAIVRV In preferred embodiment, the BCL2-BH4 domain inhibitor is a peptide comprising or consisting of the amino acid sequence SEQ ID NO:2 (Bird2). In one embodiment, the BCL2-BH4 domain inhibitor is a BCL2-BH4 domain expression inhibitor. BCL2-BH4 domain expression inhibitor for use in the present invention may be based on antisense oligonucleotide constructs. Anti-sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of TRIM24 mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of BCL2-BH4 domain proteins, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding BCL2-BH4 domain can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion. Methods for using antisense techniques for specifically alleviating gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732). Small inhibitory RNAs (siRNAs) or short hairpin RNAs (shRNAs) can also function as BCL2-BH4 domain expression inhibitor for use in the present invention. BCL2-BH4 domain gene expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that TRIM24 expression is specifically inhibited (i.e. RNA interference or RNAi). Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. et al. (2001); Hannon, GJ. (2002); McManus, MT. et al. (2002); Brummelkamp, TR. et al. (2002); U.S. Pat. Nos. 6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01 / 36646, WO 99 / 32619, and WO 01 / 68836). Inhibitors of BCL2-BH4 domain gene expression according to the present invention may be based nuclease therapy (like Talen or Crispr). The term “nuclease” or “endonuclease” means synthetic nucleases consisting of a DNA binding site, a linker, and a cleavage module derived from a restriction endonuclease which are used for gene targeting efforts. The synthetic nucleases according to the invention exhibit increased preference and specificity to bipartite or tripartite DNA target sites comprising DNA binding (i.e. TALEN or CRISPR recognition site(s)) and restriction endonuclease target site while cleaving at off-target sites comprising only the restriction endonuclease target site is prevented. The guide RNA (gRNA) sequences direct the nuclease (i.e. Cas9 protein) to induce a site-specific double strand break (DSB) in the genomic DNA in the target sequence. Restriction endonucleases (also called restriction enzymes) as referred to herein in accordance with the present invention are capable of recognizing and cleaving a DNA molecule at a specific DNA cleavage site between predefined nucleotides. In contrast, some endonucleases such as for example Fokl comprise a cleavage domain that cleaves the DNA unspecifically at a certain position regardless of the nucleotides present at this position. Therefore, preferably the specific DNA cleavage site and the DNA recognition site of the restriction endonuclease are identical. Moreover, also preferably the cleavage domain of the chimeric nuclease is derived from a restriction endonuclease with reduced DNA binding and / or reduced catalytic activity when compared to the wildtype restriction endonuclease. According to the knowledge that restriction endonucleases, particularly type II restriction endonucleases, bind as a homodimer to DNA regularly, the chimeric nucleases as referred to herein may be related to homodimerization of two restriction endonuclease subunits. Preferably, in accordance with the present invention the cleavage modules referred to herein have a reduced capability of forming homodimers in the absence of the DNA recognition site, thereby preventing unspecific DNA binding. Therefore, a functional homodimer is only formed upon recruitment of chimeric nucleases monomers to the specific DNA recognition sites. Preferably, the restriction endonuclease from which the cleavage module of the chimeric nuclease is derived is a type llP restriction endonuclease. The preferably palindromic DNA recognition sites of these restriction endonucleases consist of at least four or up to eight contiguous nucleotides. Preferably, the type llP restriction endonucleases cleave the DNA within the recognition site which occurs rather frequently in the genome, or immediately adjacent thereto, and have no or a reduced star activity. The type llP restriction endonucleases as referred to herein are preferably selected from the group consisting of: Pvull, EcoRV, BamHl, Bcnl, BfaSORF1835P, BfiI, Bgll, Bglll, BpuJl, Bse6341, BsoBl, BspD6I, BstYl, Cfr101, Ecl18kl, EcoO109l, EcoRl, EcoRll, EcoRV, EcoR124l, EcoR124ll, HinP11, Hincll, Hindlll, Hpy99l, Hpy188l, Mspl, Munl, Mval, Nael, NgoMIV, Notl, OkrAl, Pabl, Pacl, PspGl, Sau3Al, Sdal, Sfil, SgrAl, Thal, VvuYORF266P, Ddel, Eco57l, Haelll, Hhall, Hindll, and Ndel. Antisense oligonucleotides useful as BCL2-BH4 domain expression inhibitor can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and / or 3' ends of the molecule, or the use of phosphorothioate or 2'-O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone. Antisense oligonucleotides siRNAs, shRNA of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells and preferably cells expressing TRIM24. Preferably, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide siRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known to the art. Preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non- essential genes have been replaced with the gene of interest. Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in KRIEGLER (A Laboratory Manual," W.H. Freeman C.O., New York, 1990) and in MURRY ("Methods in Molecular Biology," vol.7, Humana Press, Inc., Cliffton, N.J., 1991). Preferred viruses for certain applications are the adeno-viruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in gene therapy. The adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection. In addition, wild- type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion. Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al., "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen- encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid. Some commonly used plasmids include pBR322, pUC18, pUCl9, pRC / CMV, SV40, and pBlueScript. Other plasmids are well known to those of ordinary skill in the art. Additionally, plasmids may be custom designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes. For example, the DNA plasmid can be injected by intravenous, intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun. The plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation. As used herein, the term "therapeutically effective amount" of the BCL2-BH4 domain inhibitor as above described is meant a sufficient amount to provide a therapeutic effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg / kg to about 20 mg / kg of body weight per day, especially from about 0.001 mg / kg to 7 mg / kg of body weight per day. Subject identified with a poor prognosis according to the invention can be treated with BCL2-BH4 domain inhibitor. Thus, in a particular embodiment, the subject has been identified with a poor prognosis according to the invention. Thus, in particular embodiment, the invention refers to a method for treating MYChigh- tumor in a subject in need thereof comprising i) determining the level of Inositol 1,4,5- trisphosphate receptor type 1 (ITPR1) from a sample of the patient, ii) comparing each levels determined at step i) with a predetermined reference value and iii) administering to said subject a therapeutically effective amount of BCL2-BH4 domain inhibitor when said level determined at step i) is higher than their predetermined reference value. In particular embodiment, the level of BCL2 is further determined in step i) and wherein when ITPR1 and BCL2 level are higher than their predetermined reference value, a therapeutically effective amount of BCL2-BH4 domain inhibitor is administered to said subject. In a particular embodiment, the BCL2-BH4 domain inhibitor can be administered in combination with any suitable agent, in particular with anti-MYC-amplified cancer therapy. In a particular embodiment, the classical treatment refers to radiation therapy, antibody therapy, immune checkpoint inhibitor, CAR Therapy, such as CAR T- , CAR M- or CAR NK- cell therapy, antibody-drug conjugates (ADC) or chemotherapy. In a particular embodiment, the BCL2-BH4 domain inhibitor can be administered in combination with BCL2-BH3 domain inhibitor. Accordingly, the BCL2-BH3 inhibitor may be a compound selected from the group consisting of nucleic acid (e.g., antisense oligonucleotide, siRNA or shRNA), antibodies, aptamers, polypeptides (including peptide or peptidomimetic) and small molecules. BCL2-BH3 domain inhibitors also named BH3 mimetics are well known in the art and include but are not limited to BH3 mimetic compounds such as venetoclax (ABT-199), BAU- 243, navitoclax (ABT-263), ABT-737. Other examples of BCL2-BH3 domain inhibitors include those described in the international patent publications WO / 2013 / 096059, WO / 2013 / 096060, WO / 2013 / 096055 , WO / 2013 / 096049 and WO / 2013 / 096051. In particular embodiment, the BCL2-BH4 domain inhibitor is administered in combination with venetoclax or navitoclax. As used herein, the terms “combined treatment”, “combined therapy” or “therapy combination” refer to a treatment that uses more than one medication. The combined therapy may be dual therapy or bi-therapy. For example, the combined treatment may be a combination of BCL2-BH4 domain inhibitor, such as Bird2, and BCL2-BH3 domain inhibitor, such as venetoclax. Typically, the BCL2-BH4 domain inhibitor of the present invention is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum- drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Thus the present invention also relates to a pharmaceutical composition comprising a BCL2-BH4 domain inhibitor according to the invention and a pharmaceutically acceptable carrier for use in the treatment of MYChightumors. In particular embodiment, the MYChightumor is a MYC-amplified tumors or MYCN- amplified tumors. In particular embodiment, the MYChightumor is a MYCN-amplified neuroblastoma. In particular embodiment, the MYChightumor is a MYChightumor exhibiting high level of ITPR1, and more particularly high level of ITPR1 and BCL2. In particular embodiment, the MYChightumor is a MYChighITPR1highclassified according to the method of the invention, and more particularly a MYChighITPR1highBCL2highclassified according to the method of the invention. In a particular embodiment, the NMYC-amplified cancer is a NMYC-amplified neuroblastoma. In a particular embodiment, the pharmaceutical composition further comprises a BCL2- BH3 domain. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURE: Figure 1. ITPR1 expression is high in some tumors with high BCL2 expression, especially in MYCN-amplified neuroblastomas. A. Expression of ITPR1, BCL2 and BCL2L1 (BCL-xL) genes in 965 cancer cell lines extracted from the Cancer Cell Line Encyclopedia. Correlation between ITPR1 and BCL2 or BCL1L1 levels of expression. The cancer cell lines displaying the highest expression levels of ITPR1 (>3) and of BCL2 (>3) were selected from the left-hand graph (upper right square: 54 cancer cell lines). B. Expression level of MYCN and MYC in these cancer cell lines. The 54 cancer cell lines were split into 2 categories: MYCN high, and MYCN intermediate or MYCN low. One-Way ANOVA . C. Expression data of BCL2 and ITPR1 extracted from a human neuroblastoma dataset (Tumor Neuroblastoma – SEQC – 498 – custom – ad44kcwolf) using the R2 Genomics Analysis and Visualization Platform. Correlation of expression between BCL2 and ITPR1 mRNA levels is shown in 92 MYCN- amplified neuroblastomas. Figure 2. NMYC binds ITPR1 and activates its expression in MYCN-amplified neuroblastoma cells. A. RT-qPCR of ITPR1 gene in Kelly cells treated with DMSO (negative control) or NMYC inhibitor VPC-70619. Mean + / - SEM of n = 3 independent experiments. T- test. P-values are indicated. B. RNA-seq analysis of ITPR1 expression level after 24 h of NMYC depletion in SHEP21 TET-OFF system. Wilcoxon test. P-value is shown. C. Expression data of MYCN and ITPR1 extracted from a human neuroblastoma dataset (Tumor Neuroblastoma – SEQC – 498 – custom – ad44kcwolf) using the R2 Genomics Analysis and Visualization Platform. Correlation of expression between MYCN and ITPR1 is shown in 92 MYCN-amplified neuroblastomas (left panel) and on 401 MYCN non-amplified neuroblastomas (right panel). Figure 3. High expression levels of ITPR1 are of bad prognosis in MYCN-amplified neuroblastoma and targeting ITPR1-BCL2 interaction can kill MYCN-amplified neuroblastoma cells. A. Kaplan-Meier survival curves drawn from GSE49710 dataset from patients with MYCN-amplified neuroblastoma. The 2 groups were formed according to the lowest quartile of ITPR1 expression. B-C. Cell death in Kelly and SKNAS neuroblastoma cells monitored using SYTOX Green in the first 24 h after treatment with Scrambled or Bird2 peptides. B. Representative curve over a 24 h course. Mean + / - SEM of n=3 independent experiments at 24h. Two-Way ANOVA. P-values are indicated. C. Analysis after 24 h treatment with the peptides. Mean + / - SEM of n = 3 independent experiments. Two-Way ANOVA. P-values are indicated. D. Quantification of mitochondrial calcium levels in Kelly cells overexpressing Mitycam, a mitochondrial calcium genetic sensor, in response to treatment with Scrambled or Bird2 peptides. The ratio (F1-F0) / F0 (F1: measurement 3 seconds after injection and F0: measurement 3 seconds before injection) was calculated. n = 3 independent experiments. Scrambled: n = 1,480 cells, Bird2: n = 913 cells. Mean ± SEM are shown. T-test. P-values are indicated. E. Schematic representation of the protocol used to assess Bird2 efficacy on neuroblastoma using a model of graft in the chick embryo. F. Size of the tumor in the embryo was measured through GFP fluorescence. A representative image of neuroblastoma for each condition is shown (left) and quantification of the normalized neuroblastoma volume is displayed for each embryo. Scrambled peptide n=21, Bird2 peptide n=12. Mean + / - SEM. T- test. P-values are indicated. Figure 4. Targeting ITPR1-BCL2 interaction can kill MYCN-amplified neuroblastoma organoids. A. Cell viability in neuroblastoma organoid (_O) lines 1, 2 and 3 monitored using CellTiter-Glo® assay at 72h after treatment with Scrambled or Bird2 peptides. Scrambled peptide n=9, Bird2 peptide n=9. Mean + / - STDEV. U-test. P-values are indicated. B. Live / Dead assay in neuroblastoma organoid (_O) lines 1, 2 and 3. Quantification was performed by measuring the ratio of surface area of live to dead cells (left). Representative images of live (green) / dead (red) immunofluorescence stainings of neuroblastoma organoid treated for 72h with Scrambled or Bird2 peptides. Scale bar: 200 μm. n = 4 spheres at least per condition. Representative results of two independent experiments. U-test. P-values are indicated. ITPR1 and BCL2 high cancer cell lines Cell lines Tissue of origin Type of cancer KPNYN Autonomic ganglia Neuroblastoma KELLY Autonomic ganglia Neuroblastoma CHP126 Autonomic ganglia Neuroblastoma NH6 Autonomic ganglia Neuroblastoma KPNRTBM1 Autonomic ganglia Neuroblastoma L540 Haematopoietic and lympoid tissue Hodgkin Lymphoma HDLM2 Haematopoietic and lympoid tissue Hodgkin Lymphoma JVM2 Haematopoietic and lympoid tissue Mantle Cell Lymphoma JVM3 Haematopoietic and lympoid tissue B‐Cell Prolymphocytic Leukemia EB1 Haematopoietic and lympoid tissue Burkitt Lymphoma OCIAML2 Haematopoietic and lympoid tissue Acute Myeloid Leukemia THP1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia KCL22 Haematopoietic and lympoid tissue Chronic Myeloid Leukemia, BCR‐ ABL1+ MUTZ5 Haematopoietic and lympoid tissue B‐Lymphoblastic Leukemia / Lymphoma GDM1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia MUTZ3 Haematopoietic and lympoid tissue Acute Myeloid Leukemia KG1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia L1236 Haematopoietic and lympoid tissue Hodgkin Lymphoma WSUDLCL2 Haematopoietic and lympoid tissue Diffuse Large B‐Cell Lymphoma, NOS HUT102 Haematopoietic and lympoid tissue Mycosis Fungoides MOLT16 Haematopoietic and lympoid tissue T‐Lymphoblastic Leukemia / Lymphoma NUDHL1 Haematopoietic and lympoid tissue Diffuse Large B‐Cell Lymphoma, NOS KE97 Haematopoietic and lympoid tissue Plasma Cell Myeloma PL21 Haematopoietic and lympoid tissue Acute Myeloid Leukemia P31FUJ Haematopoietic and lympoid tissue Acute Myeloid Leukemia ME1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia F36P Haematopoietic and lympoid tissue Myelodysplastic Syndromes KMS27 Haematopoietic and lympoid tissue Plasma Cell Myeloma MONOMAC6 Haematopoietic and lympoid tissue Acute Monoblastic / Monocytic Leukemia OCIAML5 Haematopoietic and lympoid tissue Acute Myeloid Leukemia HS611T Haematopoietic and lympoid tissue Hodgkin Lymphoma EHEB Haematopoietic and lympoid tissue B‐Lymphoblastic Leukemia / Lymphoma LOUCY Haematopoietic and lympoid tissue Adult T‐Cell Leukemia / Lymphoma EOL1 Haematopoietic and lympoid tissue Chronic Eosinophilic Leukemia, NOS HNT34 Haematopoietic and lympoid tissue Acute Myeloid Leukemia SIGM5 Haematopoietic and lympoid tissue Acute Monoblastic / Monocytic Leukemia NCO2 Haematopoietic and lympoid tissue Chronic Myeloid Leukemia, BCR‐ ABL1+ MOLM6 Haematopoietic and lympoid tissue Chronic Myeloid Leukemia, BCR‐ ABL1+ MONOMAC1 Haematopoietic and lympoid tissue Acute Monoblastic / Monocytic Leukemia HUNS1 Haematopoietic and lympoid tissue Plasma Cell Myeloma SKMM2 Haematopoietic and lympoid tissue Plasma Cell Myeloma MEC1 Haematopoietic and lympoid tissue Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma SUPB15 Haematopoietic and lympoid tissue B‐Lymphoblastic Leukemia / Lymphoma OCIMY5 Haematopoietic and lympoid tissue Plasma Cell Myeloma MOLM13 Haematopoietic and lympoid tissue Acute Myeloid Leukemia KASUMI1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia AMO1 Haematopoietic and lympoid tissue Plasma Cell Myeloma SKM1 Haematopoietic and lympoid tissue Acute Myeloid Leukemia GRANTA519 Haematopoietic and lympoid tissue Mantle Cell Lymphoma KO52 Haematopoietic and lympoid tissue Acute Myeloid Leukemia PLB985 Haematopoietic and lympoid tissue Acute Myeloid Leukemia KASUMI6 Haematopoietic and lympoid tissue Acute Myeloid Leukemia TUHR14TKB Kidney Renal Cell Carcinoma NCIH2172 Lung Non-Small Cell Lung Cancer Table 1 : ITPR1 expression remains high in some tumors with high MYC or NMYC and high BCL2 EXAMPLE: Methods Cell culture and reagents. MRC5 normal human embryonic lung fibroblasts and U2OS cancer cells (ATCC, Manassas, VA, USA) and virus-producing cells 293-GP and 293-T (Clontech) were cultured in Dulbecco′s modified Eagle′s medium (DMEM, Life Technologies) with GlutaMax supplemented with 10% fetal bovine serum (FBS) (Life Technologies) and 1% penicillin / streptomycin (Life Technologies). Kelly neuroblastoma cells (Sigma-Aldrich) were cultured in RPMI 1640 medium (Life Technologies) with 20% FBS (Life Technologies) and 1% penicillin / streptomycin (Life Technologies), and SKNAS neuroblastoma cells (Sigma- Aldrich) were cultured in DMEM with 10% FBS and 1% penicillin / streptomycin. All cells were grown in standard conditions (37°C, 5% CO2). Experiments were performed on Mycoplasma- negative cells. MRC5-MYC:ER cells were treated with 100 nM (Z)-4-hydroxytamoxifen (4OHT, H7904, Sigma-Aldrich) to activate MYC. Kelly cells were treated with 5 µM VPC-70619 (HY- 144878, MedChem Express) to inhibit NMYC. Kelly and SKNAS cells were treated with 20 µM of Scrambled (sequence: RKKRRQRRRGGDLNEVTCSLIVDRINPVKLY, SEQ ID NO:3) or Bird2 (sequence: RKKRRQRRRGGNVYTEIKCNSLLPLAAIVRV, SEQ ID NO:2) peptides (Smart Bioscience). Plasmids, plasmid transfection and infection. Retroviral vectors, pBabe-puro-MYC:ER43,encoding MYC oncogene fused to the ligand binding domain of the estrogen receptor (ER) (Addgene plasmid #19128), pBabe-puro (Addgene plasmid #1764)44, pLNCX2-mito-GEM-GECO1, to measure mitochondrial Ca2+ 21, were used in MRC5 cells. Lentiviral vectors pLKO.1 encoding shRNAs targeting MYCN (TRCN0000020695 for shMYCN.1 and TRCN0000020697 for shMYCN.2, Sigma-Aldrich) were used to knock down MYCN and pMOS028:Mitycam lentiviral vector (Addgene plasmid #163046)45was used to measure mitochondrial Ca2+in Kelly cells. 293-GP (for retrovirus production) or 293-T (for lentivirus production) were transfected with these plasmids in OptiMEM medium (Gibco) using PEIpro transfection reagent (Polyplus) according to the manufacturer’s recommendations. 48 h after transfection, viral supernatants were collected, diluted in DMEM (for MRC5 or U2OS cells) or RPMI 1640 (for Kelly cells) and hexadimethrine bromide (8 μg / mL, Sigma-Aldrich) was added. Viral supernatant was added to MRC5, U2OS or Kelly cells, centrifuged at 2,000 RPM for 30 min and then incubated for 8 h. 24 h after infection, selection was started using puromycin (InvivoGen) at 500 ng / mL or geneticin (Life Technologies) at 100 μg / mL. siRNA transfection. ON-TARGETplus siRNA SMARTpools of 4 siRNAs (Horizon Discovery) targeting human ITPR1, ITPR2, ITPR3, MYC, MAX, SUPT5H, TRRAP, KAT2A (GCN5), KAT5 (TIP60), RUVBL1 (TIP49) or RUVBL2 (TIP48) were used, or ON-TARGETplus non- targeting pool as negative control (siControl) (Horizon Discovery). siRNAs were incubated for 20 min with DharmaFECT 1 transfection reagent (Horizon Discovery) in antibiotics and serum- free DMEM. MRC5 or MRC5-MYC:ER cells were then reverse transfected with this mix in antibiotic-free DMEM containing 10% FBS. Final concentration of siRNAs was 15 nM. The next day, medium was changed with DMEM containing 1% antibiotics and 10% FBS. RNA extraction, reverse transcription and real-time quantitative PCR. RNAs were isolated using NucleoZol (Macherey-Nagel) following the manufacturer’s recommendations, quantified by NanoDrop One C (Thermo Fisher Scientific) and reverse- transcribed to cDNA with Maxima First Strand cDNA Synthesis Kit (Thermo Fisher Scientific) according to the manufacturer’s instructions. Real-time quantitative PCR were performed with ONEGreen FAST qPCR Premix (Ozyme) following the manufacturer’s recommendations, on a Bio-Rad CFX96 system. Primer sequences are listed in Table S2. mRNA levels of housekeeping genes GAPDH and PGK1 were used for normalization in MRC5 cells, GAPDH in U2OS cells and TBP in Kelly and SKNAS neuroblastoma cells. Relative mRNA levels were calculated using the comparative Ct (ΔΔCT) method. Western blot. After washing with 1X PBS, cells were scraped in Laemmli buffer containing 10% SDS, 10% glycerol and 1 M TrisHCl pH 6.8 and proteins in cell lysates were quantified using NanoDrop One C (Thermo Fisher Scientific). Bromophenol Blue and β-mercaptoethanol were added and samples were boiled at 95℃ for 10 min. Proteins were separated on SDS-PAGE in TG-SDS migration buffer (Euromedex) and transferred to nitrocellulose membranes (Bio-Rad). Membranes were then blocked with 5% milk in TBS with 0.01% Tween-20 (Sigma-Aldrich) TBST for 1 h at room temperature and incubated with mouse primary antibodies against ITPR1 (sc-271197, Santa Cruz Biotechnology) or α-Tubulin (T6199, Sigma-Aldrich) at 4℃ overnight with gentle shaking. After removing primary antibodies, membranes were washed three times for 10 min with TBST and incubated with anti-mouse secondary antibody conjugated to horseradish peroxidase (715-035-150, Jackson ImmunoResearch) for 1 h at room temperature, and again washed with TBST. Chemiluminescence was revealed with Clarity MAX Western ECL Substrate (Bio-Rad) for ITPR1 and Pierce ECL Western Blotting Substrate (Thermo Fisher Scientific) for α-Tubulin, using ChemiDoc XRS (Bio-Rad) and Image Lab software. Crystal violet staining, cell death analysis and senescence-associated-β- galactosidase assay. For crystal violet staining, cells were washed once with 1X PBS, fixed for 10 min with 3.7% formaldehyde (Sigma-Aldrich) and then stained with crystal violet solution (Sigma- Aldrich). For cell death analysis, the relative number of dead cells was either counted manually following cell incubation with trypan blue (Life Technologies) or monitored by Incucyte live- cell imaging system (Sartorius) following cell incubation with SYTOX Green (Thermo Fisher Scientific). Senescence-associated-β-galactosidase (SA-β-gal) assay was performed as previously described in46. The percentage of SA-β-gal-positive cells was calculated after counting at least 100 cells per condition. Mitochondrial calcium measurement. MRC5-MYC:ER cells expressing mito-GEM-GECO1, a mitochondrial calcium ratiometric gene reporter, were transfected with siRNAs and treated with 4OHT in 96-well plates. Two days after 4OHT treatment, cells were washed twice with 1X PBS and then incubated 15 min in HBSS with Ca2+and Mg2+(Life Technologies) before image acquisition. Images were acquired on a Zeiss LSM 980 confocal microscope, with one excitation performed at 405 nm and two emissions recorded at 437-499 nm and 520-755 nm. Pictures were analyzed with ImageJ-Fidji software. In each cell, fluorescence intensity was measured in three different areas. The ratio F(437-499) / F(520-755) was calculated for each area and the mean of the ratios of the three areas was calculated for each cell. Kelly cells expressing Mitycam mitochondrial calcium genetic sensor were seeded in 96-well plates in RPMI 1640 medium without red phenol. Scrambled or Bird2 peptides diluted in HBSS with Ca2+and Mg2+were added to the wells the following day. Fluorescence was recorded 50 s before peptide injection and during 5 min in total with a picture taken every 3 s. Images were acquired using Opera Phenix HCS (Perkin Elmer), with excitation at 513nm and emission recorded at 530nm and the Harmony software was used to analyze them. Fluorescence intensity was measured in three different areas per cell and the ratio (F1-F0) / F0 (F1 being the maximum fluorescence intensity after adding peptides and F0 the fluorescence intensity before adding peptides) was calculated for each area and the mean ratio of the three areas was calculated for each cell. Chick embryo model of neuroblastoma. Oncofactory SAS (an ERBC company) performed the experiments following the AVI- cellDXTM procedure described in36,47,48. Shortly 2500 Kelly-GFP cells were injected into the dorsal roof of the neural tube, in HH14 stage (E2) embryos, at the level of somites 18 to 24. The day after (E3), 10 mg / kg of control Scrambled peptide or of Bird2 peptide were intravenously injected. At HH25 (E4), embryos were harvested, weighted and measured, and a quantitative analysis of the tumor volume in each embryo was performed using 3D light sheet microscopy (Miltenyi Biotec) and Imaris software. The results are presented as a normalized tumor volume to the body surface area (BSA, calculated with the Dubois&Dubois formula). Neuroblastoma fresh tissue collection. Patient-derived xenograft models were provided by the St. Jude Children's Research Hospital. Implantation was done according to their guidelines. NSG-NOD SCID mice were obtained from Charles River animal facility. The mice were housed in sterilized filter-topped cages and maintained in the P-PAC pathogen-free animal facility (D 693880202). All animal studies were performed in strict compliance with relevant guidelines validated by the local Animal Ethic Evaluation Committee (C2EA-15) and authorized by the French Ministry of Education and Research (Authorization APAFIS#28836). Human tissue sample was obtained through a biopsy performed at Centre Léon Bérard. This sample was collected in the context of patient diagnosis. The Biological Resource Centre (BRC) of the Centre Léon Bérard (n°BB- 0033-00050) and the biological material collection and retention activity are declared to the Ministry of Research (DC-2008-99 and AC-2019-3426). The study had all necessary regulatory approvals and informed consents are available for all patients. Derivation and culture of neuroblastoma organoids. Fresh tissues were minced into small pieces and digested with collagenase D (0.125 mg / mL Roche) and 1 μg / mL DNase I (Sigma) diluted in HBSS (Gibco). After 90 min incubation at 37 °C cells were washed using advanced DMEM / F-12 medium (Gibco). Then, cultures were established in 96-well ULA plates (Corning, cat. no.7007) in a culture medium, which consists of advanced DMEM / F-12 medium (Gibco), 1X B-27 supplement without vitamin A (Gibco), 1X N2 supplement (Life), 40 ng / mL hFGF-b (Peprotech), 20 ng / mL hEGF (Peprotech), 10 ng / mL hPDGF-AA (Peprotech), 10 ng / mL hPDGF-BB (Peprotech) and 6000 U / mL heparin (Sigma). Medium was changed twice a week and neuroblastoma organoids were split every 10 days when reaching a diameter of 600-800 μm using TrypLE Express Enzyme (ThermoFisher Scientific). All cultures were tested monthly for mycoplasma using the MycoAlert® Mycoplasma Detection Kit (Lonza), in accordance with the manufacturer's instructions. Bioinformatics analysis. All genomic data were analyzed with R / Bioconductor packages, R version 4.2.2 (2022- 11-10) [https: / / cran.r-project.org / ; http: / / www.bioconductor.org / ] in a linux environment (x86_64-pc-linux-gnu [64-bit]). ChIP seq. MYC binding on the ITPR1 promoter was analyzed using publicly available ChIPseq data. The following datasets were analyzed: GSE44672, GSE86412, GSE80154, GSE80151. ChiPseq peak chromosomal locations were downloaded into R and plotted using karyoploteR package. When available ChiPseq occupancy data (i.e., wiggle and bigwig) were also downloaded and plotted. Results were presented using coverage plots, described briefly. Coverage plots: Bigwig files for each sample were used to extract the ChIPseq signal corresponding to each of the selected regions. The context given by the bottom tracks includes the chromosomal location, the annotated genes, and the “cCRE” ENCODE track. This track summarizes the ENCODE Candidate Cis-Regulatory Elements (cCREs) combined from all cell types, as described here: http: / / genome-euro.ucsc.edu / cgi- bin / hgTrackUi?hgsid=290804634_bByAayidA2MzaofYyPM9j7hRtFmU&db=mm10&c=chr 9&g=encodeCcreCombined. RNAseq. TCGA genomic data were analyzed with R / Bioconductor packages and associated packages (TCGAbiolinks, edgeR, ggplot2, singscore, msigdbr, and clusterProfiler). RNAseq data were retrieved from TCGA PanCancer and GSE80154 dataset (only focused on neuroblastoma). Survival analysis. To perform survival analysis, the dataset GSE49710 was used. It included survival information for 498 neuroblastoma patients. Kaplan-Meier survival curves were generated using survival analysis packages (survival and survminer). Log-rank tests were applied to assess differences in survival between groups. Cox proportional hazards regression models were employed to evaluate the impact of variables on survival. Stratification was performed based on MYCN amplification. Significance was set at p < 0.05. Statistical analysis. GraphPad Prism 9 was used to perform statistical analysis and create graphs, which are presented as mean of three or more independent experiments with SEM, except stated otherwise in figure legend. Statistical tests used are indicated in figure legends and p-values are indicated in each graph. Results: The MYC transcription factor directly induces ITPR1 gene expression. Based on the critical role of ITPRs and ER-mitochondria Ca2+transfer in cell death and senescence, we wanted to know whether this signaling, at the crossroad of several cell fates, could be linked to MYC activity. MRC5 normal human fibroblasts were transduced to stably express a 4OHT-inducible MYC25. In this cellular system, MYC activation or knockdown led respectively to an increase or decrease in ITPR1 mRNA levels, without significantly affecting ITPR2 and ITPR3 levels (data not shown). Given the rapid detection of ITPR1 expression, 6 hours after MYC activation, a similar timeframe to the well-known direct MYC target gene BIM26and much sooner than the induction of the well-known indirect MYC-regulated gene PUMA27,28(data not shown), we speculated that ITPR1 was a direct target for MYC. This was confirmed through ChIP-seq analysis that revealed the binding of MYC on the ITPR1 promoter in various human cells (data not shown) and on the Itpr1 promoter in mouse cells (data not shown). The transcriptional activity of MYC relied on its dimerization with its partner MAX and on the TRRAP co-factor29, as their decrease largely prevented ITPR1 upregulation by MYC (data not shown). Interestingly, the other MYC co-factors tested, namely KAT2A, KAT5, RUVBL1, RUVBL2 and SUPT5H, did not contribute to the upregulation of ITPR1 by MYC (data not shown). Together these results support that ITPR1 is a direct target gene of MYC, which induces its expression. ITPR1 mediates MYC-induced safeguard mechanisms. We then wondered whether ITPR1 contributed to MYC-induced cell death and / or senescence in normal cells. We first validated that, in addition to ITPR1 mRNA, the level of the ITPR1 protein was also regulated by MYC (data not shown). As expected, MYC activation led to a drop in the number of cells, as seen by crystal violet staining, and we observed that this drop was largely prevented by the knockdown of ITPR1 (data not shown), but not of ITPR2 or ITPR3 (data not shown). To better understand the underlying mechanisms, we then quantified the number of dying cells, through a trypan blue assay or live imaging using SYTOX dye, and the number of senescent cells using the senescence-associated-b-galactosidase (SA-b-Gal) activity assay. Knocking down ITPR1 upon MYC activation impeded both MYC-induced cell death (data not shown) and MYC-induced senescence (data not shown). Hence, these results indicate that direct upregulation of ITPR1 expression by MYC contributes to the activation of safeguard mechanisms in normal cells. ITPR1-dependent ER-mitochondria Ca2+transfer is involved in MYC-induced safeguard mechanisms. Given that Ca2+release through ITPRs channels and its subsequent accumulation in the mitochondria can contribute to cell death and cellular senescence18,23,24, we assessed mitochondrial Ca2+accumulation in MYC-activated cells using a mitochondria- targeted ratiometric Ca2+probe21,23. Strikingly, MYC induced a rise in mitochondrial Ca2+(data not shown), which was inhibited by knocking down ITPR1 or VDAC3, a channel involved in Ca2+entry into the mitochondria (data not shown). This increase in mitochondrial Ca2+induced by the MYC / ITPR1 axis was critical for MYC-induced cell death and cellular senescence, as both cell fates were inhibited after VDAC3 knockdown, similarly to ITPR1 knockdown, during MYC activation (data not shown). Altogether, in response to MYC activation, ITPR1 and mitochondrial Ca2+accumulation mediate cell death and cellular senescence, two cell fates preventing tumorigenesis. ITPR1 is largely underexpressed in cancers, and restoring the MYC / ITPR1 tumor suppressive pathway kills cancer cells. A gain-of-function of MYC is observed in most of cancers, stemming directly from gene mutations and amplifications, or indirectly through the activation of upstream oncogenic pathways and partners5. As our results support a critical, anti-tumoral role for ITPR1 by promoting cell death and cellular senescence in response to MYC activation, we hypothesized that ITPR1 may be lost in many tumors. We examined its expression profile in human cancers using TCGA datasets and observed that ITPR1 expression was significantly lower in most types of cancers compared to normal counterparts (data not shown). We then forced the activation of the MYC / ITPR1 pathway in U2OS cancer cells, in which ITPR1 expression levels are low according to the CCLE database. This led to a decrease in the number of cells and an increase in cell death, effects that were reverted by knocking down ITPR1, further supporting its tumor suppressive role (data not shown). Collectively, these data show that ITPR1 expression is low in most human cancers and that forcing the MYC / ITPR1 axis induces cancer cell death. ITPR1 expression is high in some cancer cells with high BCL2 and high MYC or MYCN expression levels, especially in MYCN-amplified neuroblastomas. Even though ITPR1 expression was relatively low in tumor tissues compared to normal tissues (data not shown), its range of expression in cancer cells was broad (Figure 1A). Given that BCL2 and BCL2L1 (BCL-xL) anti-apoptotic factors are known inhibitors of the ITPR1 channel30,31, we wondered whether cancer cells expressing high levels of ITPR1 also displayed high levels of BCL2 and / or BCL2L1 expression. BCL2 expression, but not BCL2L1 expression, was positively correlated with ITPR1 expression (Figure 1A). This suggests that cancer cells displaying high level of ITPR1 expression may have developed a strategy to decrease ITPR1 activity by upregulating BCL2. We then selected the 54 cancer cell lines with the highest BCL2 (>3) and ITPR1 (>3) expression levels (Figure 1A and Table 1). These cancer cell lines were predominantly derived from autonomic ganglia generating neuroblastoma, and from hematopoietic and lymphoid tissues, representing a wide spectrum of different cancers (Table 1), and were enriched in cancer cell lines displaying either high levels of MYCN or MYC expression or both (Figure 1B). For further experiments we focused on neuroblastoma cells lines that were all displaying MYCN amplification. Interestingly, in human neuroblastoma samples, ITPR1 and BCL2 expression levels were strongly or weakly correlated in MYCN- amplified (Figure 1C) or non-amplified (data not shown) neuroblastoma, respectively. Taken together, these observations suggest that, ITPR1 expression can be sustained in some cancer cells, especially in the context of high MYCN and / or MYC expression (especially in the case of MYCN-amplified neuroblastomas), as well as of high BCL2 expression. NMYC binds to ITPR1 and activates its expression in MYCN-amplified neuroblastomas. Next, we wondered whether NMYC could control the expression of ITPR1 in MYCN-amplified neuroblastomas. We initially examined MYCN-amplified Kelly neuroblastoma-derived cells (data not shown) and found that NMYC can bind the same region than MYC in various human cells (data not shown). Chemical inhibition of NMYC using VPC- 7061932or shRNA significantly decreased ITPR1expression (Figure 2A). We then confirmed these results using another MYCN-amplified neuroblastoma-derived cell line, SHEP, in which MYCN expression could be shut down using a TET-OFF system33,34. The shutdown led to a decrease in (i) MYCN mRNA levels (data not shown), (ii) the binding of NMYC on the ITPR1 promoter (data not shown), and (iii) the level of ITPR1 mRNA (Figure 2B). Finally, MYCN and ITPR1 mRNA levels were strongly correlated in MYCN-amplified human neuroblastoma samples and not in MYCN non-amplified neuroblastomas (Figure 2C). Hence, these results support that NMYC directly controls the expression of ITPR1 in MYCN-amplified neuroblastomas. MYCN-amplified neuroblastomas with the strongest ITPR1 expression are of worse prognosis but are vulnerable to ITPR1 activation by inhibiting ITPR1 / BCL2 interaction. Given the role of the NMYC / ITPR1 pathway in neuroblastomas, we wondered whether it was correlated with the survival of patients with either MYCN-amplified or MYCN- non-amplified neuroblastomas. As expected, patients with MYCN-amplified neuroblastomas displayed a shorter survival time (data not shown)35. Strikingly high ITPR1 expression was correlated with a worse survival in MYCN-amplified neuroblastomas (Figure 3A), but with a better survival in MYCN-non-amplified neuroblastomas (data not shown). As higher levels of ITPR1 expression in MYCN-amplified neuroblastomas correlated with worse survival and ITPR1 expression levels correlated with BCL2 expression levels, we reasoned that MYCN- amplified neuroblastoma cells might be highly sensitive to the release of ITPR1 inhibition by BCL2. To test this hypothesis, Kelly MYCN-amplified neuroblastoma cells and SKNAS MYCN non-amplified neuroblastoma cells (data not shown) were treated by Bird2 peptide, a sequence corresponding to the ITPR1 domain disrupting the ITPR1 / BCL2 interaction31, or a control peptide. Kelly cells died rapidly after Bird2 treatment whereas SKNAS cells were resistant to this treatment (Figure 3B-C). As expected, the death of Kelly cells induced by Bird2 was correlated with an increase in mitochondrial Ca2+(Figure 3D). To further confirm this result in vivo, we grafted Kelly cells stably expressing the GFP into HH14 chick embryos in the dorsal roof of the neural tube between somite 18 and 24, then injected the control or Bird2 peptide, and analyzed engrafted embryos at HH25 by 3D imaging (Figure 3E), as previously reported36. Bird2 treatment strongly decreased the size of neuroblastomas (Figure 3F). These data thus reveal that high ITPR1 expression levels are correlated with a worse prognosis in high-risk MYCN-amplified neuroblastomas, and that these neuroblastomas may be sensitive to the inhibition of the BCL2 / ITPR1 interaction. To assess the efficiency of the Bird2 therapeutic strategy in a pre-clinical model that can accurately predict outcomes in the clinic, we established neuroblastoma organoid cultures. We established 3D neuroblastoma organoids (NB_O) from MYCN-amplified patient-derived xenograft (NB1 and NB2) and human biopsy (NB3) fresh tissues (data not shown) as early as 3 days post culture-initiation. NB_O were split every 10 days (600-800μm), at a 1:2 to 1:4 ratio, for at least 6 months. These 3D models were biobanked and reanimated for further cellular and molecular analyses, with a success rate of 100% (n = 3 / 3). One of the essential points to meet the definition of tumor-derived organoid is the preservation of the cytoarchitecture of the original tissue. Thus, we further validated our models at histological level after 2 to 3 months in culture (data not shown). This phenotypic analysis revealed that NB_O preserved the histological features of their primary tumor (data not shown), including the expression of sympatho-adrenal markers observed in their parental tumors, as assessed by PHOX2B and CD56 stainings (data not shown). The robustness of patient-derived organoids also depends on their ability to preserve the molecular characteristics of their original tumor. We then performed transcriptomic characterization to assess the molecular proximity of NB_O to their corresponding tumor tissue. PCA and Pearson’s correlation heatmaps established from transcriptomic profiling unveiled that NB_O were grouped with their respective tumor-of- origin even after long term culture and cryopreservation / revival (data not shown). Hierarchical clustering analysis based on neuroblastoma sympatho-adrenal lineage-related markers confirmed the high level of similarities between NB_O and their corresponding tumor samples, even after cryopreservation, while unveiling notable differences between the NB_O lines reflecting the overall neuroblastoma inter-tumoral heterogeneity (data not shown). Finally, the three MYCN-amplified NB_O lines were treated by the Bird2 or control peptide. We observed a strong decrease in cell viability associated with a rapid death of the tumoral cells in both neuroblastoma organoid models (Figure 4A-B). REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 (2012). 2. Greer, C. et al. Myc-dependent genome instability and lifespan in Drosophila. PLoS One 8, e74641 (2013). 3. Hofmann, J. W. et al. Reduced expression of MYC increases longevity and enhances healthspan. Cell 160, 477–488 (2015). 4. Bretones, G., Delgado, M. D. & León, J. Myc and cell cycle control. Biochim Biophys Acta 1849, 506–516 (2015). 5. Madden, S. K., de Araujo, A. D., Gerhardt, M., Fairlie, D. P. & Mason, J. M. Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Mol Cancer 20, 3 (2021). 6. Lee, S., Schmitt, C. A. & Reimann, M. The Myc / macrophage tango: oncogene-induced senescence, Myc style. Semin Cancer Biol 21, 377–384 (2011). 7. McMahon, S. B. MYC and the control of apoptosis. Cold Spring Harb Perspect Med 4, a014407 (2014). 8. Charron, J. et al. Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev 6, 2248–2257 (1992). 9. Stanton, B. R., Perkins, A. S., Tessarollo, L., Sassoon, D. A. & Parada, L. F. Loss of N- myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes Dev 6, 2235–2247 (1992). 10. Zimmerman, M. W. et al. MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification. Cancer Discov 8, 320–335 (2018). 11. Berns, K., Hijmans, E. M., Koh, E., Daley, G. Q. & Bernards, R. A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts. Oncogene 19, 3330–3334 (2000). 12. Carafoli, E. & Krebs, J. Why Calcium? How Calcium Became the Best Communicator. J Biol Chem 291, 20849–20857 (2016). 13. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007). 14. Martin, N. & Bernard, D. Calcium signaling and cellular senescence. Cell Calcium 70, 16–23 (2018). 15. Martin, N., Zhu, K., Czarnecka-Herok, J., Vernier, M. & Bernard, D. Regulation and role of calcium in cellular senescence. Cell Calcium 110, 102701 (2023). 16. Kaufman, R. J. & Malhotra, J. D. Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim Biophys Acta 1843, 2233–2239 (2014). 17. Singh, S. & Mabalirajan, U. Mitochondrial calcium in command of juggling myriads of cellular functions. Mitochondrion 57, 108–118 (2021). 18. Wiel, C. et al. Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence. Nat Commun 5, 3792 (2014). 19. Ko, A. et al. Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. Cell Death Differ 25, 1050–1062 (2018). 20. Smaili, S. S., Hsu, Y. T., Youle, R. J. & Russell, J. T. Mitochondria in Ca2+ signaling and apoptosis. J Bioenerg Biomembr 32, 35–46 (2000). 21. Farfariello, V. et al. TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence. Nat Commun 13, 956 (2022). 22. Ma, X. et al. The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling. Aging Cell 17, e12831 (2018). 23. Ziegler, D. V. et al. Calcium channel ITPR2 and mitochondria-ER contacts promote cellular senescence and aging. Nat Commun 12, 720 (2021). 24. Ivanova, H. et al. Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival. Biochim Biophys Acta 1843, 2164–2183 (2014). 25. Grandori, C., Mac, J., Siëbelt, F., Ayer, D. E. & Eisenman, R. N. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo. EMBO J 15, 4344–4357 (1996). 26. Muthalagu, N. et al. BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues. Cell Rep 8, 1347–1353 (2014). 27. Michalak, E. M. et al. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ 16, 684–696 (2009). 28. Garrison, S. P. et al. Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol 28, 5391–5402 (2008). 29. Tu, W. B. et al. Myc and its interactors take shape. Biochim Biophys Acta 1849, 469– 483 (2015). 30. Rosa, N., Speelman-Rooms, F., Parys, J. B. & Bultynck, G. Modulation of Ca2+ signaling by antiapoptotic Bcl-2 versus Bcl-xL: From molecular mechanisms to relevance for cancer cell survival. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1877, 188791 (2022). 31. Rong, Y.-P. et al. Targeting Bcl-2-IP3 Receptor Interaction to Reverse Bcl-2’s Inhibition of Apoptotic Calcium Signals. Molecular Cell 31, 255–265 (2008). 32. Ton, A.-T. et al. Development of VPC-70619, a Small-Molecule N-Myc Inhibitor as a Potential Therapy for Neuroendocrine Prostate Cancer. Int J Mol Sci 23, 2588 (2022). 33. Zeid, R. et al. Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. Nat Genet 50, 515–523 (2018). 34. Lutz, W. et al. 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Claims

1. CLAIMS:

1. An in vitro method for assessing a MYChightumors patient’s risk of having a poor prognostic of survival comprising i) determining the level of Inositol 1,4,5- trisphosphate receptor type 1 (ITPR1) from a sample of the patient, ii) comparing the level determined at step i) with a predetermined reference value and iii) concluding that the patient will have a short survival time when said level determined at step i) are higher than their predetermined reference value.

2. The method of claim 1, wherein the MYChightumors is a MYCNhightumors 3. The method of claim 1 or 2, wherein the tumor is kidney cancer or lung cancer. In a particular embodiment, the cancer is selected from the group consisting of neuroblastoma, hodgkin lymphoma, mantle cell lymphoma, B-cell prolymphocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, B‐ lymphoblastic leukemia / lymphoma, T‐lymphoblastic leukemia / lymphoma, diffuse large B‐cell lymphoma, mycosis fungoides, plasma cell myeloma, myelodysplastic syndromes, acute monoblastic / monocytic leukemia, T‐cell leukemia / lymphoma, chronic eosinophilic leukemia, acute monoblastic / monocytic leukemia, chronic lymphocytic leukemia / small lymphocytic, renal cell carcinoma and non-small cell lung cancer.

4. The method of claim 2, wherein the tumor is MYCN-amplified neuroblastoma.

5. The method of any claims 1 to 4, wherein the level of BCL2 can further be determined in step i), and wherein it is concluding in step iii) that the patient will have a short survival time when each levels of ITPR1 and BCL2 are higher than their predetermined reference value.

6. A method for treating MYChighcancer in a subject in need thereof comprising administering a therapeutically effective amount of an inhibitor of the BH4 domain of BCL2.

7. The method of claim 6, wherein the MYChighcancer is a MYChighand ITPR1highcancer, an more particularly a MYChigh, ITPR1highand BCL2highcancer.

8. The method of claim 6 or 7, wherein the subject has been identified with a poor prognosis according to claim 1 to 5.

9. The method of claim 6 to 8, wherein the MYChightumor is selected from the group consisting of neuroblastoma, hodgkin lymphoma, mantle cell lymphoma, B-cell prolymphocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, B‐lymphoblastic leukemia / lymphoma, T‐lymphoblastic leukemia / lymphoma, diffuse large B‐cell lymphoma, mycosis fungoides, plasma cell myeloma, myelodysplastic syndromes, acute monoblastic / monocytic leukemia, T‐cell leukemia / lymphoma, chronic eosinophilic leukemia, acute monoblastic / monocytic leukemia, chronic lymphocytic leukemia / small lymphocytic, renal cell carcinoma and non-small cell lung cancer.

10. The method of claim 9, wherein the MYChightumor is a NMYC-amplified neuroblastoma.

11. The method of claim 6 to 10, wherein the BH4 domain of BCL2 is a peptide comprising or consisting of the amino acid sequence SEQ ID NO:2 (Bird2).

12. The method of claim 6 to 11, wherein the BH4 domain of BCL2 is administered in combination with any suitable agent, in particular with anti-MYChighcancer therapy.

13. The method of claim 12, wherein the BH4 domain of BCL2 is administered in combination with a BCL2-BH3 domain inhibitor.

14. The method of claim 13, wherein the BCL2-BH3 domain inhibitor is venetoclax or navitoclax.

15. A pharmaceutical composition comprising a BCL2-BH4 domain inhibitor according to the invention and a pharmaceutically acceptable carrier for use in the treatment of MYChighcancer.

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