Analyses of relationship between clonal hematopoiesis associated with leukemia-related gene mutations and leukemia/solid tumors/cardiovascular diseases
| Project/Area Number |
18K19558
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
合山 進 東京大学, 医科学研究所, 准教授 (80431849)
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
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| Keywords | クローン性造血 / 動脈硬化 / HHEX / LDLレセプター / 白血病 / 心血管系疾患 / 固形癌 |
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| Outline of Final Research Achievements |
We demonstrate that mutant ASXL1 (ASXL1-MT) induces DNA damage via activation of BAP1, de-ubiquitination and activation of Akt1 using a clonal hematopoiesis mouse model expressing ASXL1-MT. This work has at least partly clarified the molecular mechanisms underlying the frequent progression of clonal hematopoiesis to hematological malignancies. In addition, we have also clarified that combination of ASXL1-MT-KI and LDLR knockout (LDLR-KO) followed high fat diet significantly enhances atherosclerosis when compared to that of LDLR-KO.
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| Academic Significance and Societal Importance of the Research Achievements |
健常高齢者の末梢血において白血病と同じ遺伝子変異を1つ有する造血（クローン性造血）は65歳以上の人で10人に1人に検出される。クローン性造血は造血器腫瘍発症リスクを10倍上昇させるが、脳梗塞、心筋梗塞など心血管異常も約2倍多いことが報告されており、こちらが生命予後に関与する。癌患者の４人に１人がクローン性造血を有し、クローン性造血を有する人は有意に癌の再発率が高く予後が悪いこと報告された。これらの現象の分子機序解明は、高齢化社会において重要な課題である。
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Report
(2 results)
Research Products
(11 results)
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[Presentation] Mutant ASXL1 Promotes Expansion of the Phenotypic Hematopoietic Stem Cell Compartment2019
Author(s)
Takeshi Fujino, Susumu Goyama, Yuki Sugiura, Daichi Inoue, Satoshi Yamasaki, Akiko Matsumoto, Naru Sato, Hironobu Morinaga, Shiori Shikata, Tomofusa Fukuyama, Yosuke Tanaka, Shuhei Asada, Tsuyoshi Fukushima, Hiroaki Honda, Emi K Nishimura, Tatsuhiro Shibata, Makoto Suematsu ,Toshio Kitamura
Organizer
The 61st American Society of Hematology annual meeting
Related Report
Int'l Joint Research
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