| Project/Area Number |
15H04855
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
北浦 次郎 順天堂大学, 医学(系)研究科(研究院), 先任准教授 (30282651)
井上 大地 東京大学, 医科学研究所, 特任助教 (80735746)
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| Co-Investigator(Renkei-kenkyūsha) |
Fukuyama Tomofusa 東京大学, 医科学研究所, 助教 (10300906)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
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| Keywords | エピジェネティクス / MDS / ASXL1 / EZH2 / 白血病 / ABC-G2 / 骨髄ストローマ細胞 / クローン性造血 / 骨髄異形性症候群 / 遺伝子 / ノックインマウス / 造血器腫瘍 |
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| Outline of Final Research Achievements |
Myelodysplastic syndromes are a group of heterogeneous diseases, associated with a variety of gene mutations. In this work, we attempted to elucidate the molecular basis of MDS pathogenesis, by focusing on the mutations of epigenetic factors.ASXL1 mutations (ASXL1-MT) globally reduced histone H3K4me3, leading to reduced functions of hematopoietic stem cells, and differentiation block of erythroid cells. Our knock-in mouse of ASXL1-MT can be a good model for pre-MDS or clonal hematopoiesis.
An EZH2 mutant lacking its SET domain induced an MDS-like disease in mouse MDS model, via derepression of ABC-G2 induced by reduction of H3K27me3. We found that ABC-G2, known as a hematopoietic stem cells, is specifically expressed at higher levels in MDS among hematological malignancies. Interestingly, overexpression of ABC-G2 alone induced an MDS-like disease in mouse BMT model. These results suggest that ABC-G2 expression plays pivotal roles in MDS pathogenesis.
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