| Project/Area Number |
17K09929
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kumamoto University |
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Principal Investigator |
Iwanaga Eisaku 熊本大学, 大学院生命科学研究部(医), 助教 (90743675)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 急性白血病 / CEBPA / DMR / IKZF1 / Myeloid-T白血病 / ゲノム |
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| Outline of Final Research Achievements |
We focused on another differentially methylated region (DMR) of CEBPA and identified a novel control element. Using databases, we identified a conserved DMR in the CEBPA 3′-untranslated region (UTR). Myeloid cell lines with elevated CEBPA expression were negative for CEBPA 3′-UTR methylation. The 3′-UTR was methylated, and CEBPA expression was strongly suppressed, in non-myeloid cell lines. Methylation analysis of 231 AML cases showed that hypermethylation of the 3′-UTR was associated with AML that had a myeloid/NK/T-cell phenotype, down-regulated CEBPA, and immature CD7/CD56 positive phenotype. Furthermore, we discovered that the CEBPA 3′-UTR DMR could enhance transcription from the CEBPA native promoter. In vitro experiments identified IKZF1 binding sites in the 3′-UTR that are responsible for this increased transcription of CEBPA. These results indicate that the CEBPA 3′-UTR DMR is a positive regulatory element of CEBPA related to myeloid/NK/T-cell lineage leukemogenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
CEBPA-3’UTRメチル化型のCD7/CD56陽性Myeloid/NK/T白血病は簡便な検出法も含め我々が初めて報告する病型である。今回同定した一群はNOTCH1変異陰性やCD56陽性が特徴的でありMyeloid-T白血病の中でもさらにNKもしくは樹状細胞系への分化傾向を持った白血病である可能性があり新しい疾患概念の候補として興味深い。CEBPA遺伝子の3’非翻訳領域（UTR）がCEBPAに対する調節因子として作用しリンパ系転写因子IKZF1が結合することを明らかにした。このように骨髄性白血病においてもリンパ系の転写因子が白血化に関与していることは新たな治療戦略を作るうえで参考になりうる。
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