2023 Fiscal Year Final Research Report
Elucidation of epigenetic regulation mechanism of myeloid neoplasms with atypical 3q26 translocation toward therapeutic applications
| Project/Area Number |
21K08414
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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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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | 非定型3q26転座型骨髄性腫瘍 / EVI1 (MECOM) 活性化 / エンハンサーハイジャック / 疾患特異的iPS細胞 / BET阻害剤 |
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| Outline of Final Research Achievements |
In this study, we created a pathological model using iPS cells generated from MDS patients with the t(3;8)(q26.2;q24) translocation. iPS cell-derived MDS cells showed similar EVI1 (MECOM) expression changes, H3K27 acetylation patterns of the EVI1 promoter/enhancer and MYC blood enhancer cluster as the original patient MDS cells. Furthermore, we revealed that the BET inhibitor JQ1 induces apoptosis in iPS cell-derived MDS cells by suppressing EVI1 activation. The results of this research demonstrate the usefulness of iPS cell models in elucidating the detailed mechanism of enhancer hijacking due to chromosome structural changes and in searching for therapeutic drug candidates.
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| Free Research Field |
血液腫瘍
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| Academic Significance and Societal Importance of the Research Achievements |
本研究成果は、非定型EVI1転座型骨髄性腫瘍の詳細な病態解明及び治療薬候補探索におけるiPS細胞モデルの有用性を示すものであり、予後不良なEVI1 (MECOM) 高発現骨髄性腫瘍の治療抵抗性・再発に対する新規治療の基盤に繋がると考えられる。
さらにこの疾患iPS細胞を用いた新しいプラットフォームは、骨髄性腫瘍のみならずエンハンサーハイジャック（染色体の転座や遺伝子増幅などによりエンハンサーが本来制御すべき遺伝子とは異なる遺伝子を制御するようになり、がん細胞の増殖や生存に関わる遺伝子の発現亢進を引き起こすこと）が関与する腫瘍性疾患全体に応用できる可能性がある。
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