Control of myelofibrosis targeting the amplification mechanism of CALR mutant stem cells and the functional motif of CALR mutant proteins

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08819
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Shide Kotaro 宮崎大学, 医学部, 助教 (20468028)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 骨髄増殖性腫瘍 / 原発性骨髄線維症 / 造血幹細胞

Outline of Final Research Achievements

We created the first blood cell-specific Calreticulin (Calr) KO mouse that had not yet been developed, and clarified the role of Calr in hematopoiesis. We further showed that haploinsufficiency of the Calr gene enhances the competitive repopulation capacity of hematopoietic stem cells (HSCs), and also enhances the clonal expansion of HSCs with CALR mutations in myeloproliferative patients.
Regarding the mechanism of cell proliferation by CALR mutant protein, we found a sequence essential for tumorigenicity in vitro and in vivo in the amino acid sequence specific to the mutant protein. We plan to begin preclinical studies targeting these amino acids.

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(primary myelofibrosis:PMF) 、および本態性血小板血症(essential thrombocythemia:ET)に続発する二次性骨髄線維症(post-ET MF)患者の5年生存率は40%と予後不良であり、PMF, post-ET MFには臨床的なunmet needsがある。この疾患群のドライバー変異であるcalreticulin(CALR)の変異は造血幹細胞レベルで生じており、約3割の患者にみられる。本研究の成果は、CALR変異が疾患を引き起こす仕組みを明らかにしたものであり、これらの患者群を対象とした新規治療開発の基盤となるものである。