Comprehensive elucidation of MDS (myelodysplastic syndromes) pathogenesis
| 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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Report
(4 results)
Research Products
(41 results)
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[Journal Article] Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation2018
Author(s)
Nagase R, Inoue D, Pastore A, Fujino T, Hou HA, Yamasaki N, Goyama S, Saika M, Kanai A, Sera Y, Horikawa S, Ota Y, Asada S, Hayashi Y, Kawabata KC, Takeda R, Tien HF, Honda H, Abdel-Wahab O, Kitamura T.
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Journal Title
The Journal of Experimental Medicine
Volume: 印刷中
Issue: 6
Pages: 1729-1747
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A novel ASXL1?OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies2018
Author(s)
Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, Li Z, Matsui H, Kanai A, Saika M, Yamaguchi R, Kozuka-Hata H, Kawabata KC, Yokoyama A, Goyama S, Inaba T, Imoto S, Miyano S, Xu M, Yang FC, Oyama M, Kitamura T.
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Journal Title
Leukemia
Volume: 印刷中
Issue: 6
Pages: 1327-1337
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD).2016
Author(s)
Kitamura T, Watanabe-Okochi N, Enomoto Y, Nakahara F, Oki T, Komeno Y, Kato N, Doki N, Uchida T, Kagiyama Y, Togami K, Kawabata KC, Nishimura K, Hayashi Y, Nagase R, Saika M, Fukushima T, Asada S, Fujino T, Izawa Y, Horikawa S, Fukuyama T, Tanaka Y, Ono R, Goyama S, Nosaka T, Kitaura J, Inoue D
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Journal Title
Journal of Biochemistry
Volume: 159
Issue: 1
Pages: 17-25
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-C(m)) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-C(m).2015
Author(s)
Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC, Nagase R, Horikawa S, Izawa K, Fukuyama T, Nakahara F, Oki T, Harada Y, Harada H, Aburatani H, Kitamura T.
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Journal Title
Exp Hematol.
Volume: 43(4)
Issue: 4
Pages: 300-308
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.2015
Author(s)
Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
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Journal Title
Leukemia
Volume: 29(4)
Issue: 4
Pages: 847-57
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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