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Mutant calreticulin for the diagnosis of myeloid malignancies

A malignant tumor, calreticulin technology, applied in the field of medical use of inhibitors, can solve problems such as lack of molecular markers

Pending Publication Date: 2016-08-31
CEMM FORSCHUNGSZENT FUR MOLEKULARE MEDIZIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although advances have been made in the understanding of the molecular pathogenesis of MPN, about half of patients with PMF and ET lack molecular markers for diagnosis because these patients are negative for both JAK2 and MPL mutations

Method used

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  • Mutant calreticulin for the diagnosis of myeloid malignancies
  • Mutant calreticulin for the diagnosis of myeloid malignancies
  • Mutant calreticulin for the diagnosis of myeloid malignancies

Examples

Experimental program
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Effect test

Embodiment 1

[2029] Example 1: Somatic Mutations of Calreticulin in Primary Myelofibrosis and Essential Thrombocythemia

[2030] Materials and methods

[2031] patient sampling

[2032] We studied patients with Philadelphia chromosome-negative myeloproliferative neoplasms at the Medical University of Vienna, Austria, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The study was approved by the ethics committees of both institutions, and all patients provided written informed consent. Diagnosis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis was made according to the World Health Organization's 2008 criteria (Sverdlow et al, 2008).

[2033] Diagnostic criteria

[2034] Diagnosis of polycythemia vera, essential thrombocythemia and primary myelofibrosis was made according to the criteria being used at the time of first observation, as previously reported (Passamonti et al. 2004). In 2002, the World Health Organizat...

Embodiment 2

[2113] Example 2: Generation of CALR mutant-specific antibodies in mice

[2114] CALR mutations associated with MPN occur in the last exon (exon 9) of the gene. These mutations are insertions and / or deletions which result in "frameshift" mutations to very specific alternative reading frames, resulting in the synthesis of novel C-terminal peptides in the mutants. Since all mutations resulted in the same alternative reading frame, the C-terminal peptide had the same sequence in all CALR mutants.

[2115] The c-terminal sequence (sequence- RRKMSPARPRTSCREACLQGWTEA -) synthetic peptides were used to immunize four wild-type C57B1 / 6 mice.

[2116] Mice received 3 booster doses after the primary immunization. Mouse sera were tested for the presence of mutant calreticulin-specific antibodies (pre-immunization and after booster doses) by Western blot analysis of lysates from HEK cells overexpressing CALR del52 and exon 9-deficient artificial Generated CALR mutant (Δexon9, which ...

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Abstract

The present invention relates to a method for diagnosing myeloid malignancy comprising determining the presence of a mutant allele of the calreticulin gene. Also genomic sequences, cDNA sequences, mRNA sequences and protein sequences of the mutant calreticulin are subject of the present invention. Further, the invention relates to medical uses of inhibitors of mutant calreticulin.

Description

technical field [0001] The present invention relates to a method for diagnosing myeloid malignancies comprising determining the presence of a mutant allele of the calreticulin gene. In addition, the genome sequence, cDNA sequence, mRNA sequence and protein sequence of the mutant calreticulin are also the object of the present invention. Furthermore, the present invention relates to the medical use of inhibitors of mutant calreticulin. Background technique [0002] Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are monoclonal hematologic abnormalities belonging to the classic BCR-ABL-negative myeloproliferative neoplasms (MPNs) (Campbell & Green, 2006). Since the discovery of somatic mutations in the JAK2 kinase gene in 2005, tremendous advances have been made in the molecular diagnosis, clinical management, treatment, and molecular understanding of MPN. The valine to phenylalanine (V617F) mutation constitutively activates the Jak2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47C12Q1/68
CPCC12Q2600/156C12Q1/6886A61P35/00A61P35/02C12Q1/6869G01N33/57426G01N2333/47G01N2800/50C12Q2600/158A61K39/0005C07K14/4728C07K16/18C12N15/113C07K2317/76C12N2310/14C12Q2600/172G01N2333/4727
Inventor 罗伯特·克拉洛维奇托尔斯滕·克兰普夫尔海因茨·吉斯林格
Owner CEMM FORSCHUNGSZENT FUR MOLEKULARE MEDIZIN
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