2022 Fiscal Year Final Research Report
Mechanisms of developing refractory leukemia
Project/Area Number |
20K08745
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | Hokkaido University |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | FLT3-ITD |
Outline of Final Research Achievements |
For the mechanism of FLT3-ITD formation, we tested the hypothesis that palindrome-like structures in FLT3 exon14 form higher structures that are susceptible to genomic damage, thereby giving rise to ITDs. We confirmed that artificial ITDs can be generated in human and mouse cell lines by inducing genomic damage to the FLT3-ITD accumulation site using CRISPR. Using clinical samples, we found that multiple small clone-sized FLT3-ITDs were generated even in patients with clinically FLT3-ITD-negative AML. On follow-up analysis, we found that the FLT3-ITD clones expanded in some cases that relapsed resulting in FLT3-ITD acquisition at relapse.
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Free Research Field |
Clinical Hematology
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Academic Significance and Societal Importance of the Research Achievements |
以前は急性骨髄性白血病(AML)においてFLT3-ITD変異が存在すること自体が予後不良と考えられていたが、アリル頻度が高いFLT3-ITDを持つことが予後不良と関連することが知られるようになった。本研究ではAMLの約半数では微小FLT3-ITDを含めたFLT3-ITDが存在することを示し、従来臨床上捉えられていた以上の割合の症例がFLT3-ITDを持つことを明らかにした。FLT3-ITDの生成機構やクローン拡大機構の解明は、疾患発生機序の理解、および最適な治療戦略の開発に重要である。
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