2022 Fiscal Year Final Research Report
Molecular mechanisms of leukemic cell engraftment and expansion in vivo
| Project/Area Number |
19H01035
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 50:Oncology and related fields
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| Research Institution | Tokyo Medical University (2022)
Japanese Foundation for Cancer Research (2019-2021) |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | 急性骨髄性白血病 / 骨髄内定着 / Bcl11a / Trib1 / Hoxa9 / 転写制御 / スーパーエンハンサー / Erg |
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| Outline of Final Research Achievements |
The goal of this study is to identify important genes in embedding and progression of acute myeloid leukemia (AML) in vivo. Functional genomic screening using shRNAs and sgRNAs was performed in bone marrow transplantation experiments with mouse AML cells, and Rnf20 was identified as a responsible gene for bone marrow engraftment of AML. Also, the study clarified that Bcl11a suppresses the transcriptional activity of PU.1 in malignant transformation of AML, and identified Asb2 as an important Bcl11a arget gene. Moreover, the study revealed the role of Trib1 in Hoxa9-associated super-enhancer regulation to induce up-regulation of Erg.
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| Free Research Field |
腫瘍生物学 血液学
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| Academic Significance and Societal Importance of the Research Achievements |
白血病の骨髄定着と生体内進展を規定する分子機構を明らかにする目的で本研究を遂行した。機能遺伝学的スクリーニングや、Bcl11a、Trib1の重要性を明らかにするとともに、解析手法としてin vivoにおけるAML発症やAML細胞と間質細胞との相互作用を重視したことから、Asb2によるフィラミンAの調節作用やErg遺伝子の同定といった重要な下流遺伝子を同定し、白血病のin vivoにおける進展機構の理解に資する結果を示した。さらに、エピゲノム阻害薬であるJQ1やHDAC阻害薬、LSD1阻害薬の有効性を検証し、今後のAMLに対する新たな治療法の開発に繋がる成果を得た。
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