Role of CALR mutation in the pathogenesis of myeloproliferative neoplasms and rogue hematopoietic signaling

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09852
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Shide Kotaro 宮崎大学, 医学部, 助教 (20468028)
• Research Collaborator: KAMEDA Takuro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨髄線維症 / 骨髄増殖性腫瘍 / マウスモデル

Outline of Final Research Achievements

We analyzed Calreticulin (CALR), which is frequently mutated in essential thrombocythemia and primary myelofibrosis. The role of CALR in normal hematopoiesis and the mechanism by which mutant CALR causes MPN were elucidated in in vitro experiments and in in vivo experiments by creating multiple mouse models. We found that CALR mutation conferred cell proliferation and cytokine independence and caused mice to develop essential thrombocythemia. However, at the same time, it also became clear that they have a negative effect on hematopoietic stem cells, suggesting that maintenance of mutated hematopoietic stem cells and development of disease require elements other than CALR mutation.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

原発性骨髄線維症の予後は5年生存率40%と不良であり、新規治療法へのアンメットメディカルニーズがある。CALR変異は原発性骨髄線維症の約3割の患者で認められることから治療標的として注目されている。本研究で見出したCALR変異による疾患発症の仕組みは、原発性骨髄線維症を始め、同じくCALR変異を有する本態性血小板血症の克服、治癒を目指した治療法開発につながる成果という意味で極めて意義が大きい。