2022 Fiscal Year Final Research Report
Functional analysis of the tandem duplication mutation RUNX1 in leukemogenesis
Project/Area Number |
20K08201
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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 52050:Embryonic medicine and pediatrics-related
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Research Institution | Hirosaki University |
Principal Investigator |
Toki Tsutomu 弘前大学, 医学研究科, 講師 (50195731)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | 小児白血病 / ダウン症 / RUNX1 / GATA1 |
Outline of Final Research Achievements |
In Down syndrome caused by trisomy 21, 5 to 10% of newborns develop a preleukemic condition called transient abnormal myeloproliferative disorder (TAM). Most of these cases remit spontaneously, but about 20% of cases develop acute myeloid leukemia (ML-DS) within 4 years. In about 20% of cases, a partial tandem duplication mutation of RUNX1 (RUNX1-PTD) was found at the time of progression to ML-DS. In this study, we investigated the molecular biological function of this novel mutation. The results showed that RUNX1-PTD has abnormal transcriptional activation and subcellular localization compared to the wild type. Knock-in mouse studies confirmed that, unlike the previously reported RUNX1 mutation, this mutation delayed the onset of leukemia at an early stage.
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Free Research Field |
血液学
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Academic Significance and Societal Importance of the Research Achievements |
白血病の発症機構を探索する際, 発症以前の状態を観察することは疾患特性から困難を要する。しかしML-DSの場合, ダウン症を背景にTAMからML-DSへの進展は, トリソミー21とGATA1変異に加えて, 本研究で焦点を当てた RUNX1-PTD 変異などの付加が原因になっていることを示した。この様な発見は, 白血病の多段階発症のメカニズムを明らかにする上で, 非常に重要である。加えて, RUNX-PTD 変異は, 他の RUNX1遺伝子変異と異なり, 極めて早期に白血病を引き起こすことを発見した。この知見はCBF-AMLの発症機構の解明にも資するものである。
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