Elucidation of the molecular pathogenesis of myeloproliferative neoplasms with CALR mutations for the development of novel therapeutic strategies.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Kitanaka Akira 川崎医科大学, 医学部, 教授 (70343308)
• Co-Investigator(Kenkyū-buntansha): 通山 薫 川崎医科大学, 医学部, 教授 (80227561)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 骨髄増殖性腫瘍 / calreticulin / チロシンキナーゼ

Outline of Final Research Achievements

In this study, we attempted to identify key molecules in the intracellular signaling mechanism by which mutant CALR activates MPL-mediated signaling. We found that the Src-selective inhibitor PP2 and the Bcr-Abl/Src inhibitor bosutinib suppressed the proliferation of F-36P-MPL cells expressing CALR mutant and decreased the transcriptional activity of STAT5, which was enhanced by the expression of mutated CALR, in 293T cells. Of note, bosutinib inhibited cell proliferation at clinically achievable concentrations. Specific supression of Lyn, a major Src family member in hematopoietic cells, inhibited mutant CALR-dependent cell proliferation, indicating that Lyn may play an important role in the signaling mechanism by mutant CALR.

Free Research Field

細胞内情報伝達機構

Academic Significance and Societal Importance of the Research Achievements

近年、骨髄増殖性腫瘍（MPN）の病態解明が著しく進歩し、病因となる変異遺伝子産物を標的とした新規薬剤JAK阻害薬が臨床応用されている。JAK阻害薬はMPN症例の多くに変異が認められるJAK2を標的としており、臨床症状の改善に有効であるが、血球減少の副作用がある。疾患の発症・進展に関与する変異型JAK2と、正常な造血の維持に必要な野生型JAK2の間で酵素活性を有する部分の構造に差異はなく、両者に異なった作用を示す阻害薬の開発は極めて困難である。本研究で見出した変異CALR下流分子の詳細を解明することは、これまでと異なった作用機序のMPN治療薬開発につながる可能性がある。