| Project/Area Number |
12557078
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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 | 展開研究 |
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| Research Field |
Hematology
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| Research Institution | Dokkyo University School of Medicine |
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Principal Investigator |
MITANI Kinuko Dokkyo University School of Medicine, Department of Hematology, professor, 医学部, 教授 (50251244)
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| Co-Investigator(Kenkyū-buntansha) |
MAKI Kazuhiro Dokkyo University School of Medicine, Department of Hematology, assistant professor, 医学部, 助手 (50337391)
WAGA Kazuko Dokkyo University School of Medicine, Department of Hematology, lecturer, 医学部, 講師 (00285917)
NAKAMURA Yuichi Dokkyo University School of Medicine, Department of Hematology, lecturer, 医学部, 講師 (20227896)
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| Project Period (FY) |
2000 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Keywords | AML1 / EVI-1 / TGBβ / CtBP / conditional knock-out mice / MEN / ノックアウト / ノックインマウス / 胎生致死 / ドミナント・ネガティブ効果 / 造血幹細胞腫瘍 / 白血病 / C / EBPα / ノックイン / ノック・イン / コンディショナル / Lck / Creリコンビネース / 胸腺 / モデルマウス / ノックイン・マウス / MLL |
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| Research Abstract |
1.AML1/EVI-1 is a chimeric transcription factor that plays a causative role in blastic transformation of chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS). AML1/EVI-1 repressed transcription through PAI-1promoter that was activated by TGFI3 signals. AML1/EVI-1specifically bound to an intracellular signal transducer of TGFβ, Smad3, and inhibited its functions. Because AMLI/EVI-1 bound to a corepressor CtBP, recruitment of histone deacetylase could be an underlying mechanism. AML1/EVI-1 also interfered with AMIL 1-mediated transcription through association with CtBP. Moreover, AML1/EVI-l blocked differentiation of 32D cells induced by G-CSF, depending on the CtBP-binding region in EVI-l portion. These data indicate that AMLI/EVI-1progresses CML or MIDS to acute leukemia partly through abolishing TGFβ signals and blocking AML1 functions.
2.We assessed the requirement of AML 1 in adult hematopoiesis using an inducible gene-targeting method. In the absence of AML 1, hematopoietic progenitors were fully maintained with normal myeloid development. However, AML 1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T-and B-lymphocyte development. These data indicate that AML1 is required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells in adult hematopoiesis.
3.We generated knock-out mice of MEN. They were embryonic lethal, and die before E6.5 and after implantation. MEN was found to play a non-redundant role as an elongation factor in postimplantation development of mice.
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