2018 Fiscal Year Final Research Report
Mechanisms of leukemogenesis by the leukemia-driving enhancer
| Project/Area Number |
15H02507
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
鈴木 未来子 東北大学, 医学系研究科, 講師 (80508309)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | 染色体転座 / 白血病 / GATA2 / EVI1 |
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| Outline of Final Research Achievements |
Chromosomal rearrangement between 3q21 and 3q26 provokes leukemia with poor prognosis. The rearrangement induces misexpression of both misexpression of EVI1 gene and reduction of GATA2 gene expression by translocation of the GATA2 gene enhancer. Here we asked whether GATA2 haploinsufficiency in addition to EVI1 misexpression contributed to leukemogenesis by using a 3q21q26 mouse model that recapitulates the GATA2 enhancer-driven EVI1 misexpression coupled with a Gata2 heterozygous deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemogenesis. While EVI1-misexpressed blast-like cells retained some limited ability to differentiate into myeloid cells, simultaneous loss of one Gata2 allele suppressed the myeloid differentiation and promoted the expansion of these blast-like cells. These results demonstrate that Gata2 heterozygous deletion accelerates EVI1 misexpression leukemia by inducing proliferation and differentiation defect of leukemia cells.
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| Free Research Field |
腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
3番染色体転座・逆位を伴う白血病は予後不良群に分類されており、未だ有効な治療法は確立されていない。本研究成果からEVI1遺伝子の高発現だけでなく、エンハンサーの提供元であるGATA2遺伝子の発現減少が白血病の悪性化に寄与していることが明らかとなり、EVI1遺伝子（またはその下流因子）だけでなく、GATA2遺伝子（またはその下流因子）も治療標的となることが期待される。
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