| Project/Area Number |
20K08747
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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 | Tohoku University |
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Principal Investigator |
Suzuki Mikiko 東北大学, 医学系研究科, 准教授 (80508309)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | GATA2 / EVI1 / 白血病 / 転座 / 逆位 / エンハンサー / 染色体転座 / 染色体逆位 / 3q / MECOM |
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| Outline of Research at the Start |
3番染色体の転座・逆位は、急性骨髄性白血病の予後不良因子である。この転座・逆位を伴う白血病では、GATA2遺伝子エンハンサーの移動により、EVI1遺伝子とGATA2遺伝子の発現量に異常が起こることが白血病発症の原因となる。本研究では、EVI1とGATA2の量のバランス（EVI1-GATA2バランス）に着目し、この難治白血病の発症機構および悪性化機構の解明を目指す。
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| Outline of Final Research Achievements |
Chromosome 3 translocation/inversion is a known poor prognostic factor in acute myeloid leukemia. In these alleles, the proto-oncogene EVI1 on 3q26 is highly expressed by the GATA2 gene enhancer on 3q21, which is responsible for leukemogenesis. Using reporter mice to monitor EVI1 gene expression regulated by the inverted allele, we found that the inverted allele-derived EVI1 gene is highly expressed in both hematopoietic stem cells (HSCs) and progenitor cells, whereas the endogenous EVI1 gene is specifically expressed in HSCs. Since leukemic cells arise not only from HSCs but also from progenitor cells in the mice with the inverted allele, the altered EVI1 gene expression pattern due to translocation/inversion confers the ability to generate leukemic cells not only from HSCs but also from progenitor cells.
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| Academic Significance and Societal Importance of the Research Achievements |
3番染色体転座・逆位によりGATA2遺伝子エンハンサーを獲得したEVI1遺伝子は、造血幹細胞だけでなく造血前駆細胞にも高発現し、白血病の起源となる細胞数を大幅に増加させていることが明らかとなった。染色体転座・逆位に伴う原がん遺伝子の発現量増加のみでなく、発現細胞種の変化によっても白血病発症がもたらされることを示しており、白血病発症における新たな知見を提供した。
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