Multistep leukemogenesis caused by imbalanced GATA1 function
| Project/Area Number |
15H04759
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
平野 育生 東北大学, 医学系研究科, 助教 (00708117)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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| Keywords | 白血病 / 転写因子 / GATA転写因子 / 遺伝子改変マウス / Rasシグナル / がん / 遺伝子 / 癌 / E2F |
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| Outline of Final Research Achievements |
Somatic GATA1 gene mutations leading to the production of GATA1s that lacks the amino-terminal transactivation domain is both requisite and sufficient for the development of the preleukemic condition referred to as transient myeloproliferative disorder (TMD) for acute megakaryoblastic leukemia (AMKL) in Down-syndrome newborns. We have established mice exclusively expressing GATA1s which phenocopy the human TMD. In this research, we found that reduced apoptosis and increased proliferation capacities in GATA1s megakaryocyte progenitors are involved in the pathogenesis of TMD. We also found that megakaryocyte progenitors with relatively lower level of GATA1s reduced in differentiation potency, consequently the progenitors persistently stay in mice and the mice are prone to develop leukemia. Higher amount of GATA1s expression partially compensates the defect in megakaryocyte maturation mediated through the Ras signaling cascade and enable progenitors to pass quickly without transformation.
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| Academic Significance and Societal Importance of the Research Achievements |
遺伝子変異の蓄積が白血病をはじめとするがんの発症機構に関わっていると考えられている。本研究では、GATA1転写因子の質的異常と量的異常の両方がそれぞれ異なった分子メカニズム（増殖・分化・細胞死調節）の破綻を引き起こし、それらの異常の複合として白血病発症に至ることを明らかにした。本解析により、多段階発がん機構においてさらなる理解が進むものと考えられる。
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Report
(5 results)
Research Products
(39 results)
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[Journal Article] Monitoring of minimal residual disease in early T-cell precursor acute lymphoblastic leukaemia by next-generation sequencing2016
Author(s)
Pan X, Nariai N, Fukuhara N, Saito S, Sato Y, Katsuoka F, Kojima K, Kuroki Y, Danjoh I, Saito R, Hasegawa S, Okitsu Y, Kondo A, Onishi Y, Nagami F, Kiyomoto H, Hozawa A, Fuse N, Nagasaki M, Shimizu R, Yasuda J, Harigae H, Yamamoto M
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Journal Title
Br J Haematol
Volume: in press
Issue: 2
Pages: 318-321
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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