The molecular mechanisms of leukmogenesis by GATA1
| Project/Area Number |
17390295
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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 |
Pediatrics
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| Research Institution | Hirosaki University |
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Principal Investigator |
ITO Etsuro Hirosaki University, Hirosaki University, Graduate School of Medicine, Professor (20168339)
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| Co-Investigator(Kenkyū-buntansha) |
TOKI Tsutomu Hirosaki University, Graduate School of Medicine, Lecturer (50195731)
高橋 良博 弘前大学, 医学部, 助手 (10333725)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2007: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥6,300,000 (Direct Cost: ¥6,300,000)
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| Keywords | GATA1 / leukemia / transcription factor / Down syndrome / TMD / KIT / 21番染色体 / RUNX1 |
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| Research Abstract |
We performed this study to understand the molecular mechanisms of leukemogenesis by GATA1, and found the following results.
1. To clarify the functional differences between GATA1 and GATA1 mutant, we constructed the retroviral expression vector for GATA1/estrogen receptor (ER) fusion protein and transduced a Stem cell factor (SCF)-dependent Down syndrome-associated acute megakaryoblastic leukemia (DS-AMKL) cell line. Conditional activation of both GATA1/ER and GATA1s/ER with Tamoxifen resulted in the growth inhibition and down-regulation of KIT expression.
2. We demonstrate the abundant expression of KIT in all transient myeloproliferative disorder (TMD) patients examined. SCF stimulated the proliferation of the blast cells and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation effectively in vitro. To investigate the signal cascade downstream from the SCF/KIT pathway, we analyzed a DS-AMKL cell line. SCF activated the RAS/MAPK and PI3K/AKT pathways in this cell line, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. These results suggest the essential role of SCF/KIT signaling in the proliferation of DS-related leukemia.
3. The RUNX1 gene is localized to chromosome 21, within the critical region for DS. In this study, we show that GATA1 binds to RUNX1 through its zinc-finger domains, and that the C-finger is indispensable for synergy with RUNX1. All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1bα promoter, whereas the levels of transcriptional activities were diverse among the mutants. Thus our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.
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Report
(4 results)
Research Products
(41 results)
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[Journal Article] Transgenic expression of Bach1 transcription factor results in megakaryocytic impairment.2005
Author(s)
Toki T, Katsuoka F, Kanezaki R, Xu G, Kurotaki H, Sun J, Kamio T, Watanabe S, Tandai S, Terui K, Yagihashi S, Komatsu N, Igarashi K, Yamamoto M, Ito E.
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Journal Title
Blood 105
Pages: 3100-3108
Related Report
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[Presentation] Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome.2007
Author(s)
Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kamio T, Kojima S, Kiyoi H, Mano H, Ito E.
Organizer
The 49^<th> ASH meeting
Place of Presentation
Atlanta, Georgia
Description
「研究成果報告書概要(和文)」より
Related Report
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[Presentation] Molecular mechanisms of TAM development2007
Author(s)
Ito E, Xu G, Kanezaki R, Toki T.
Organizer
The 17^<th> Annual meeting of Japanese Society for Obstetrics and Gynecology, and Pediatric Hematology
Place of Presentation
Toyama, Japan
Description
「研究成果報告書概要(欧文)」より
Related Report
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