| Project/Area Number |
14370308
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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 |
Hematology
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| Research Institution | Dokkyo Medical University |
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Principal Investigator |
MITANI Kinuko Dokkyo Medical University School of Medicine, Department of Hematology, Professor, 医学部, 教授 (50251244)
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| Co-Investigator(Kenkyū-buntansha) |
WAGA Kazuo Dokkyo Medical University School of Medicine, Department of Hematology, Lecturer, 医学部, 講師 (00285917)
SASAKI Ko Dokkyo Medical University School of Medicine, Department of Hematology, Assistant Professor, 医学部, 助手 (60282638)
MAKI Kazuhiro Dokkyo Medical University School of Medicine, Department of Hematology, Assistant Professor, 医学部, 助手 (50337391)
中村 裕一 獨協医科大学, 医学部, 講師 (20227896)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2004: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | TEL / AML1 / PTPRR / transcription factor / leukemia / chromosomal abnormality / ERK / isoform / UT-7 / GM細胞 / ベンチジン / PPO / t(12;21) / ドミナント・ネガティブ / inv(12) / ドミナント・ネガティブ効果 / 12p13 / ETS / リン酸化 |
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| Research Abstract |
Regulation in hematopoiesis by TEL.
(1)We demonstrated that TEL stimulates the erythroid differentiation induced by chemical compounds hemin and DMSO in murine erythroleukemia MEL cells. To confirm this TEL's effect in a more physiological setting, we introduced TEL cDNA into human leukemia UT7/GM cells. TEL accelerated the erythroid differentiation induced by erythropoietin and inhibited the megakaryocytic differentiation induced by thrombopoietin. These data suggest that TEL could decide the cell fate in differentiation in erythroid/megakaryocytic common progenitor.
(2)We also examined regulatory mechanisms in the TEL's function. TEL was found to be phosphorylated by the MAP kinase ERK. Hyperphosphorylated TEL lost its transcription repressive ability and tumor suppressive function, and exerted dominant-negative effect over hypophosphorylated TEL. On the other hand, various types of isoform were observed expressed from the TEL gene. Among them, ΔHLH and ΔETS isoforms were dominant-inhibitory molecules for wild-type TEL. We showed that expression frequency of ΔETS isoform was increased in myelodysplastic syndrome-derived leukemia in comparison to myelodysplastic syndrome in early phase.
Mechanism in leukemogenesis by TEL.
(1)TEL/AML1 generated by t(12;21) in childhood pre-B cell acute lymphoblastic leukemia is known to dominantly repress wild-type AML1's function. We showed that TEL/AML1 also inhibits wild-type TEL's function. Loss of tumor suppressive function from TEL could pay a causative role in leukemogenesis by t(12;21).
(2)We cloned a novel TEL/PTPRR chimeric gene generated by inv(12) in acute myelogenous leukemia. TEL/PTPRR had dominant-negative function over wild-type TEL in molecular assays. Furthermore, UT7/GM cells overexpressing TEL/PTPRR acquired factor-independent growth, and maintained high level of phosphorylation in STAT3 even after factor withdrawal. We conclude that TEL/PTPRR causes leukemia through inactivating TEL and stimulating STAT3 signal.
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