| Project/Area Number |
19K17834
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Miyazaki |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | MPN / ET / myelofibrosis / CALR / EZH2 / TET2 / primary myelofibrosis / EZH / 骨髄増殖性腫瘍 / エピゲノム異常 / CALR変異 |
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| Outline of Research at the Start |
骨髄増殖性腫瘍(myeloproliferative neoplasms: MPN) に分類される本態性血小板血症(essential thrombocythemia; ET)、原発性骨髄線維症(primary myelofibrosis; PMF)の症例で共通してみられるCalreticulin(CALR)変異やJAK2変異と、EZH2やTET2などのエピゲノム異常を併せ持つマウスモデルを作成する。表現型の違いや白血病への移行の頻度を解析し、MPNにおけるエピゲノム異常の役割やAMLへの急性転化の際の分子病態を明らかにする。
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| Outline of Final Research Achievements |
We generated CALR mutant mice and CALR mutant/EZH2-deficient mice. Both developed ET, but did not develop myelofibrosis or leukemia, and their survival time was equivalent to that of wild type mice.
Next, We performed competitive transplantation with CALR mutant LSKs or CALR mutant/EZH2-deficient LSKs. Although none of them developed ET, we observed increased percentage of donor-derived cells the mice transplanted with CALR mutant LSK or CALR mutant/EZH2-deficient LSK. No difference in chimerism was observed between CALR mutant/EZH2-deficient LSK transplanted mice and CALR mutant LSK transplanted mice. We found that EZH2 deficiency for CALR mutations does not affect progression to MF or the differentiation potential of stem cells.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、骨髄増殖性腫瘍ではドライバー遺伝子の種類によってエピゲノム異常の与える影響が異なる事が明らかとなった。この結果により、CALR変異をもつ骨髄増殖性腫瘍の発症や急性転化に寄与するエピゲノム異常を同定し、新規治療薬の開発につながる事が期待できる。また、骨髄増殖性腫瘍患者のドライバー遺伝子やエピゲノム遺伝子変異の種類により予後の層別化を行い、新たな治療戦略の開発につながる事が期待される。
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