Pharmaceutical composition for treating acute megakaryoblastic leukemia and primary myelofibrosis

Abstract

To provide a pharmaceutical composition for treating acute megakaryoblastic leukemia and primary myelofibrosis.SOLUTION: The present invention provides a pharmaceutical composition for treating a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis, the pharmaceutical composition comprising an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating acute megakaryoblastic leukemia and primary myelofibrosis.

Background Art

[0002] Hitherto, for the treatment of acute megakaryoblastic leukemia (AMKL), combination chemotherapy mainly using anthracycline and cytarabine has been used. Although remission may be achieved by such combination chemotherapy, since it targets proliferation, the side effects are large, and 10 to 20% of the patients who have received combination chemotherapy have a poor prognosis, and an expansion of treatment options, particularly the expansion of molecular target therapy, has been demanded.

[0003] For example, in Non-Patent Document 1, it has been shown that Aurora A kinase is a treatment target for acute megakaryoblastic leukemia, but the drug group used in Non-Patent Document 1 has not received pharmaceutical approval. In view of such a situation, there has been a need for a novel molecular target therapy with development superiority.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a pharmaceutical composition for treating a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis.

Means for Solving the Problems

[0006] In the research on identifying treatment targets for myelodysplastic syndromes, the inventors newly discovered that crizotinib, which is approved for the treatment of ALK fusion gene-positive non-small cell lung cancer, promotes megakaryocyte maturation in patients with myelodysplastic syndromes, leading to the development of a new treatment method for thrombocytopenia. On the other hand, in the bone marrow of patients with acute megakaryoblastic leukemia (AMKL), which corresponds to the FAB classification M7 of acute myeloid leukemia (AML), the number of blasts showing megakaryocytic characteristics (hereinafter also referred to as "megakaryoblasts") increases, and these cells can be regarded as immature abnormal megakaryocytes. Therefore, when the inventors examined the effect of crizotinib on the AMKL cell line, they newly discovered that crizotinib induces maturation and cell death in the cell line. As a substance having a similar effect, alisertib, an Aurora A kinase inhibitor (a substance not approved for pharmaceutical use), is known, and since it shows a therapeutic effect at the animal level, it was considered that crizotinib would also show a therapeutic effect. That is, the inventors first discovered the new activity of approved crizotinib, namely, the therapeutic effect on AMKL through megakaryocyte maturation and cell death (Figure 1).

[0007] Furthermore, the inventors also considered that myelofibrosis, which is thought to be caused in part by an increase in abnormal megakaryocytes in the bone marrow, may have a therapeutic effect through the maturation and / or cell death of abnormal megakaryocytes. The present invention was made based on these findings.

[0008] That is, the present invention provides: [1] A pharmaceutical composition for the treatment of a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof; [2] The pharmaceutical composition according to [1], which is for oral administration; [3] A cell maturation and / or cell death inducer comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof, wherein the cell is selected from megakaryoblastic leukemia cells and abnormal megakaryocytes. [4] A composition for inducing cell maturation and / or cell death in a subject, wherein the composition comprises an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof, wherein the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes, wherein the subject has 20% or more blasts in total nucleated cells of peripheral blood or bone marrow, and 50% or more of the blasts show megakaryocyte characteristics, or has a myelofibrosis lesion, a composition; [5] The composition according to [4], wherein the subject is a mammal; [6] The composition according to [4] or [5], wherein the mammal is selected from the group consisting of humans, monkeys, mice, rats, cows, horses, sheep, dogs, and cats relating thereto.

Effect of the Invention

[0009] According to the present invention, a pharmaceutical composition for treating a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis can be provided.

Brief Description of the Drawings

[0010]

Figure 1

Modes for Carrying Out the Invention

[0011] Hereinafter, the modes for carrying out the present invention will be specifically described. The present invention is not limited to the following embodiments, and various modifications can be made and implemented within the scope of the gist thereof.

[0012] The first aspect of the present invention relates to a pharmaceutical composition for the treatment of a disease selected from acute megakaryoblastic leukemia (AMKL) and primary myelofibrosis. The pharmaceutical composition contains an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof.

[0013] Crizotinib is a compound having the chemical name 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. In the present specification, crizotinib is intended to include (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine and (S)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. Crizotinib is preferably (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. Crizotinib may be synthetic or a commercial product, and examples of commercial products include, but are not limited to, PF-02341066.

Chemical formula

[0014] In the present specification, derivatives of crizotinib are intended to include a group of compounds containing a pyridine ring substituted with an amine. Specifically, derivatives of crizotinib are a group of compounds containing 3-isopropoxypyridin-2-amine, and more specifically, a group of compounds containing 3-(1-phenylethoxy)pyridin-2-amine.

Chemical formula

[0015] Derivatives of crizotinib are represented, for example, by the above formula (I). In this specification, derivatives of crizotinib also include both the (R) form and the (S) form, similar to crizotinib. In formula (I), the pyridine ring is substituted with an -NR1R2 group. R1 and R2 may be the same or different and are each selected from the group consisting of hydrogen, cyano, -CHO, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 9 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 9 halogen atoms, C2-C4-alkenyl, and C2-C4-alkynyl (wherein the hydrogen atoms of the alkyl, alkoxy, alkenyl, and alkynyl may be replaced by -OH).

[0016] The pyridine ring may further be substituted with a substituent A selected from 5- to 7-membered aromatic groups and cycloaliphatic groups. In this case, for example, the 1st, 2nd, 3rd, 4th, 5th, or 6th position of the pyridine ring is substituted by the substituent A. The substituent A is preferably selected from 5- to 6-membered aromatic groups and cycloaliphatic groups, and more preferably selected from 5-membered aromatic groups. The aromatic groups and cycloaliphatic groups include heterocyclic groups, and one or more heteroatoms selected from S, N, and O form the heterocyclic ring together with carbon atoms.

[0017] Examples of the substituent A include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl.

[0018] The substituent A is unsubstituted or substituted by one or more substituents B. When a plurality of substituents B are present, they may be the same or different. The substituent B is selected from the following (b1) and (b2): (b1) A chain hydrocarbon group selected from the group consisting of halogen, cyano, -CHO, -OH, -COOH, C1-C4 alkyl, C1-C4 halogenoalkyl having 1 to 9 halogen atoms, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenoalkoxy having 1 to 9 halogen atoms, C2-C4 alkenyl, and C2-C4 alkynyl (wherein the hydrogen atoms of the alkyl, alkoxy, alkenyl, and alkynyl may be replaced by -OH). (b2) A cyclic hydrocarbon group selected from the group consisting of aromatic groups and cycloaliphatic groups having 4 to 7 members. Here, the aromatic group and the cycloaliphatic group include a heterocyclic group, and one or more heteroatoms selected from S, N, and O form the heterocyclic ring together with carbon atoms.

[0019] When the substituent B is a cyclic hydrocarbon group (in the case of (b2) above), it may be unsubstituted or substituted by one or more selected from the group consisting of cyano, -CHO, -OH, C1-C4 alkyl, C1-C4 halogenoalkyl having 1 to 9 halogen atoms, C1-C4 alkoxy, C1-C4 halogenoalkoxy having 1 to 9 halogen atoms, C2-C4 alkenyl, C2-C4 alkynyl, and C1-C4 alkoxy-C1-C4 alkyl.

[0020] Examples of the substituent B include, but are not limited to, a piperidinyl group, a pyridinyl group, a pyrrolyl group, a pyrazolyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. Here, preferably, 1 to 4 hydrogen atoms of the alkyl group are replaced by -OH.

[0021] In the derivative of crizotinib, the benzene ring may be substituted by one or more substituents X. When a plurality of substituents X are present, they may be the same or different. The substituent X is selected from the following (x1) and (x2): (x1) A chain hydrocarbon group selected from the group consisting of halogen, cyano, -CHO, -OH, -COOH, C1-C4 alkyl, C1-C4 halogenoalkyl having 1 to 9 halogen atoms, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenoalkoxy having 1 to 9 halogen atoms, C2-C4 alkenyl, and C2-C4 alkynyl (wherein the hydrogen atoms of the alkyl, alkoxy, alkenyl, and alkynyl may be replaced by -OH); (x2) A cyclic hydrocarbon group selected from the group consisting of aromatic groups and cycloaliphatic groups having 4 to 7 members. Here, the aromatic group and the cycloaliphatic group include a heterocyclic group, and one or more heteroatoms selected from S, N, and O form the heterocyclic ring together with carbon atoms.

[0022] Examples of the substituent X include, but are not limited to, an imidazolyl group, a pyrazolyl group, a thiadiazolyl group, a thiazolyl group, a triazolyl group, F, Cl, Br, I, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.

[0023] Examples of the derivative of crizotinib include, but are not limited to, PF-06439015.

[0024] In acute megakaryoblastic leukemia (AMKL), megakaryoblastic leukemia cells come to occupy much of the bone marrow, and when there are, for example, 20% or more blasts in the total nucleated cells of peripheral blood or bone marrow, and 50% or more of these blasts show the characteristics of megakaryocytes, it is diagnosed as acute megakaryoblastic leukemia. The blasts (megakaryoblasts) showing the increased megakaryocytic characteristics in the bone marrow of patients with acute megakaryoblastic leukemia are considered to be immature abnormal megakaryocytes. Therefore, when the present inventors allowed crizotinib, which has an effect of promoting megakaryocyte maturation, to act on an AMKL cell line, it was found that crizotinib induces maturation and cell death in the cell line (Figure 1). Therefore, the pharmaceutical composition according to the present invention treats acute megakaryoblastic leukemia through the induction of maturation and cell death of crizotinib against AMKL cells.

[0025] On the other hand, it is known that the onset of myelofibrosis can be caused by an increase in abnormal megakaryocytes in the bone marrow and it also co-occurs with acute megakaryoblastic leukemia. As evidence that abnormal megakaryocytes in the bone marrow can contribute to myelofibrosis, for example, mice overexpressing the gene Thpo encoding thrombopoietin develop fibrosis associated with an increase in the number of megakaryocytes (Reference 1). Similarly, administration of thrombopoietin to mice also causes severe myelofibrosis (Reference 2). In addition, in mice with specific deletion of the gene Gata1 encoding a transcription factor in megakaryocytes, the number of immature megakaryocytes in the bone marrow increases and severe fibrosis is observed (References 3 and 4). On the other hand, alisertib, an Aurora A kinase inhibitor, induces differentiation and maturation of malignant undifferentiated megakaryocytes in acute megakaryoblastic leukemia and exhibits a therapeutic effect (Reference 5), but it has also been shown to induce differentiation and polyploidization of abnormal megakaryocytes and reduce myelofibrosis in a mouse model of primary myelofibrosis (Reference 6). That is, substances that promote differentiation and maturation of abnormal megakaryocytes can have a therapeutic effect not only on acute megakaryoblastic leukemia but also on primary myelofibrosis. Therefore, crizotinib, its derivatives or pharmaceutically acceptable salts thereof can treat myelofibrosis through the maturation and / or cell death of abnormal megakaryocytes.

[0026] As used herein, the term "treatment" encompasses both therapeutic treatment and prophylaxis, the purpose of which is to prevent or delay (mitigate) an undesirable physiological change or disorder. In the context of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, stabilization of a disease state (i.e., not exacerbating), delay or deceleration of disease progression, improvement or temporary remission of a disease state, remission (including partial and complete remission), whether or not detectable. Subjects in need of treatment include those who already have the condition or disorder, as well as those who are susceptible to the condition or disorder, or those in whom the condition or disorder should be prevented. In a preferred embodiment, "treatment" is, for example, the promotion of cell maturation and cell death as compared to a control. Here, the cell is at least one selected from megakaryoblastoid leukemia cells and abnormal megakaryocytes. Megakaryoblastoid leukemia cells refer to tumor cells that increase in the bone marrow with megakaryoblastoid leukemia. Abnormal megakaryocytes do not necessarily appear with megakaryoblastoid leukemia, are abnormal in morphology and / or function, and refer to megakaryocytes in an immature state. Also included in abnormal megakaryocytes are cases where there is no morphological or functional abnormality but there is a significant quantitative increase in cells.

[0027] In this specification, the term "cell maturation" shall include cell differentiation in addition to cell maturation. When the cell is an abnormal megakaryocyte, the maturation of the cell can be confirmed, for example, by evaluating megakaryocyte nuclear ploidy. Specifically, the cell of interest can be fixed, stained with a nuclear staining reagent, and confirmed by using a flow cytometer that the nuclear ploidy of the cell is increasing. Conversely, the suppression of megakaryocyte maturation can be confirmed by the same method using a flow cytometer that the nuclear ploidy of the cell is decreasing. The differentiation of megakaryocytes can be confirmed, for example, by the expression level of surface antigens CD41, CD61, CD42, or CD36. Specifically, the cell of interest can be stained with an antibody against the above antigen, and confirmed by using a flow cytometer that the antigen expression level of the cell is increasing. The maturation of megakaryocytes can also be confirmed by morphological observation of bone marrow cells. The maturation, maturation suppression, and differentiation of megakaryoblast leukemia cells can also be confirmed by the same method.

[0028] The cell death of megakaryocytes can be confirmed, for example, by staining the cells with a dye for cell viability determination and detecting the stained dead cells using a flow cytometer. The cell death of megakaryoblast leukemia cells can also be confirmed by the same method.

[0029] Preferably, the pharmaceutical composition according to the present invention is for oral administration. The pharmaceutical composition according to the present invention may be formulated, for example, into tablets, powders, granules, capsules, solutions, etc., but is not limited thereto.

[0030] The pharmaceutical composition according to the present invention may typically contain pharmaceutically acceptable additives, for example, excipients, binders, lubricants, solvents, diluents, stabilizers, isotonic agents, etc. known in the art.

[0031] The composition according to the present invention may be used as a combination agent combined with a further pharmaceutical composition. Regarding the combination agent, the components in each pharmaceutical composition (i.e., the first active ingredient and the second active ingredient) may be administered together, sequentially, or individually, in one combined unit dosage form or two separate unit dosage forms. A therapeutically effective amount of each active ingredient of the combination agent according to the present invention may be administered simultaneously, individually, or in any order, sequentially or continuously. In the combination agent, the first active ingredient and the second active ingredient may be present in a plurality of units. The combination agent includes, for example, a kit containing each active ingredient and instructions for use.

[0032] A second aspect of the present invention relates to an agent for inducing cell maturation and / or cell death, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof. Here, the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes.

[0033] For example, crizotinib, its derivatives, and pharmaceutically acceptable salts thereof may induce the maturation of the cells. Thus, in one aspect, the present invention relates to an agent for inducing cell maturation, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof.

[0034] For example, crizotinib, its derivatives, and pharmaceutically acceptable salts thereof may induce cell death of the cells. Thus, in one aspect, the present invention relates to an agent for inducing cell death, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof.

[0035] Preferably, crizotinib, its derivatives, and pharmaceutically acceptable salts thereof may induce both cell maturation and cell death of the cells. Thus, in a preferred aspect, the present invention relates to an agent for inducing cell maturation and cell death, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof.

[0036] A third aspect of the present invention is a composition for inducing cell maturation and / or cell death in a subject, wherein the composition comprises an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof, the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes, the subject is there are 20% or more blasts in the total nucleated cells of peripheral blood or bone marrow, and 50% or more of these blasts exhibit megakaryocyte characteristics, or has a myelofibrosis lesion, relates to a composition.

[0037] In one aspect, the subject has increased blasts in the total nucleated cells of peripheral blood or bone marrow compared to a healthy subject. The subject has an increase in blasts, for example, 5%, preferably 10%, more preferably 15%, still more preferably 20%, and even more preferably 25% compared to a healthy subject, and 50% or more of these blasts exhibit megakaryocyte characteristics.

[0038] That the subject has increased blasts in peripheral blood or bone marrow compared to a healthy subject and that the blasts exhibit megakaryocyte characteristics can be confirmed by morphologically and / or immunologically analyzing peripheral blood or bone marrow cells obtained by blood sampling or bone marrow aspiration by various staining methods.

[0039] In one aspect, having increased blast cells in peripheral blood or bone marrow compared to a healthy subject, and many of those blast cells showing megakaryocyte characteristics, means that the subject is suffering from acute megakaryoblastic leukemia. In this specification, in such a case, the subject is also said to "have megakaryoblastic leukemia cells". In this aspect, the composition according to the present invention is a composition for inducing cell maturation and / or cell death in a subject, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof, wherein the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes, and the subject has 20% or more blast cells in the total nucleated cells of peripheral blood or bone marrow, and 50% or more of said blast cells show megakaryocyte characteristics.

[0040] In one aspect, the subject has a myelofibrosis lesion. The fact that the subject has a myelofibrosis lesion can be confirmed by subjecting bone marrow tissue obtained by bone marrow biopsy to silver staining or trichrome staining, etc., to visualize excessive collagen and osteosclerosis. In this aspect, the composition according to the present invention is a composition for inducing cell maturation and / or cell death in a subject, comprising an active ingredient selected from the group consisting of crizotinib, its derivatives, and pharmaceutically acceptable salts thereof, wherein the cells are abnormal megakaryocytes, and the subject has a myelofibrosis lesion.

[0041] The subject is a vertebrate, preferably a mammal. As used herein, the term "mammal" is used to refer to any animal classified as a mammal, and is selected from, for example, but not limited to, the group consisting of humans, monkeys, mice, rats, cows, horses, sheep, dogs, and cats. In a preferred aspect, the subject is a human.

[0042] The crizotinib contained in the pharmaceutical composition according to the present invention acts on acute megakaryoblastic leukemia cells and / or abnormal megakaryocytes, and induces maturation and cell death. Therefore, by administering the pharmaceutical composition according to the present invention to a patient having megakaryoblastic leukemia cells and / or abnormal megakaryocytes, maturation and cell death of megakaryoblastic leukemia cells and / or abnormal megakaryocytes can be induced. That is, treatment of acute megakaryoblastic leukemia by drug repositioning becomes possible.

[0043] In addition, since crizotinib can be taken orally, it is a treatment option that does not increase the burden on patients and medical staff.

[0044] So far, it has been shown that Aurora A kinase is a therapeutic target for acute megakaryoblastic leukemia (for example, reference 5), but the tested drug groups have not received drug approval. On the other hand, since the present invention contains crizotinib, which has already been approved for the treatment of ALK fusion gene-positive non-small cell lung cancer, as an active ingredient, it can be said that it is a novel molecular target therapy with development advantages in the treatment of acute megakaryoblastic leukemia.

[0045] In addition, it has also been shown that Aurora A kinase is a therapeutic target for primary myelofibrosis (for example, reference 6), but the tested drug groups have not received drug approval. On the other hand, since the present invention contains crizotinib, which has already been approved for the treatment of ALK fusion gene-positive non-small cell lung cancer, as an active ingredient, it can be said that it is a novel molecular target therapy with development advantages in the treatment of primary myelofibrosis.

Example

[0046] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited by these examples at all.

[0047] Samples used in the examples were prepared and each measurement was performed according to the following procedures.

[0048] [Cell culture] The acute megakaryoblastic leukemia cell line CMK86 cells were maintained and cultured in RPMI medium containing 10% FBS.

[0049] [Evaluation of megakaryocyte nuclear ploidy] The cells were fixed with ice-cold 70% ethanol. After washing the fixed cells with buffer (PBS containing 2% FBS and 2 mM EDTA), they were stained with anti-CD41 / CD61 antibody (Biolegend). Staining was performed with PI, a nuclear staining reagent, and the nuclear ploidy of CD41 / CD61-positive cells was evaluated using a flow cytometer CytoFLEX (Beckman Coulter).

[0050] [Evaluation of megakaryocyte differentiation] The cells were stained with anti-CD41 antibody (Biolegend) and anti-CD42b antibody (Biolegend), and the proportion of CD42b-positive cells in live cells was evaluated using a flow cytometer CytoFLEX (Beckman Coulter).

[0051] [Evaluation of cell death] The cells were stained with LIVE / DEAD™ Fixable Violet Dead Cell Stain Kit (Thermo), and the proportion of dead cells was evaluated using a flow cytometer FACSCelesta (BD Biosciences).

[0052] <1>Addition of crizotinib to the acute megakaryoblastic leukemia cell line To the acute megakaryoblastic leukemia cell line CMK86 cells cultured according to the above method, DMSO as a solvent or 1 μM crizotinib (MedChemExpress (MCE)) was added, and after 72 hours, nuclear ploidy, megakaryocyte differentiation, and cell death were evaluated by flow cytometry. The evaluation results of nuclear ploidy, megakaryocyte differentiation, and cell death are shown in Figures 1A, 1B, and 1C, respectively.

[0053] From Figures 1A to 1C, it was shown that crizotinib induces differentiation maturation and cell death in the acute megakaryoblastic leukemia cell line.

[0054] (References) Reference 1: Villeval, J.L. et al. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood 90,4369 - 4383,1997 Reference 2: Maekawa, T. et al. Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.Leukemia 31,2709 - 2716,2017 Reference 3: Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A. & Orkin, S.H. A lineage - selective knockout establishes the critical role of transcription factor GATA - 1 in megakaryocyte growth and platelet development. EMBO J. 16,3965 - 3973,1997 Reference 4: Vannucchi, A.M. et al. Development of myelofibrosis in mice genetically impaired for GATA - 1 expression (GATA - 1low mice). Blood 100,1123 - 1132,2002 Reference 5: Wen, Q. et al. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 150,575 - 589,2012 Reference 6: Wen, Q. J. et al. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med. 21, 1473-1480, 2015

Industrial Applicability

[0055] By administering the composition according to the present invention, a novel molecular targeted therapy for acute megakaryoblastic leukemia and primary myelofibrosis can be provided.

Claims

1. A pharmaceutical composition for the treatment of a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis, comprising an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof.

2. The pharmaceutical composition according to claim 1, which is for oral administration.

3. A cell maturation and / or cell death inducer comprising an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof, wherein the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes.

4. A composition for inducing cell maturation and / or cell death in a subject, wherein the composition comprises an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof, wherein the cells are selected from megakaryoblastic leukemia cells and abnormal megakaryocytes, wherein the subject is a subject having 20% or more blasts in the total nucleated cells of peripheral blood or bone marrow, and 50% or more of the blasts showing megakaryocyte characteristics, or a subject having a myelofibrotic lesion.

5. The composition according to claim 4, wherein the subject is a mammal.

6. The composition according to claim 4 or 5, wherein the mammal is selected from the group consisting of human, monkey, mouse, rat, cow, horse, sheep, dog, and cat.

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