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造血幹細胞腫瘍白血病化の分子機構の解析

Research Project

Project/Area Number 08261204
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

三谷 絹子  東京大学, 医学部・附属病院, 助手 (50251244)

Co-Investigator(Kenkyū-buntansha) 小川 誠司  東京大学, 医学部・附属病院, 医員
宮川 清  東京大学, 医学部・附属病院, 助手 (40200133)
Project Period (FY) 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1996: ¥2,500,000 (Direct Cost: ¥2,500,000)
Keywords骨髄異形成症候群 / t(11;19)(q23;p13.1) / MLL / MEN / 転写因子 / 伸長因子
Research Abstract

造血幹細胞腫瘍白血病化の分子機構の一端を明らかにする目的で進展期MDS症例に観察されるt(11;19)(q23;p13.1)の原因遺伝子MLL/MENの解析を行った。MLLはAT hooksと2つのzinc finger domainsを有する転写因子であり、t(11;19)転座の結果、2つのzinc finger domainsを失っている。一方、MENは849個のアミノ酸をコードする新規遺伝子であり、t(11;19)転座の結果、N末の45個のアミノ酸を失っている。その後、MENはRNAポリメラーゼII伸長因子をコードしていることが報告された(Shilatifard,A.,et al.,Science 271,1873-1876,1996)。私たちは、MLL/MEN、tMLL(患者白血病細胞で発現が期待される2つのzinc finger domains以下のシークエンスを失った短縮型のMLL)、MENのcDNAをCos7細胞に遺伝子導入し、それぞれ230kD,180kD,80kDの蛋白質として発現することを明らかにした。免疫組織染色及び細胞分画の実験により、これらの蛋白質はすべて主に核内に存在することが明らかになった。さらに、MENの生物学的機能を解析する目的でMEN及びlysine rich domainを欠いたMENの欠失変異体cDNAをRatl細胞に遺伝子導入した。この結果、MENはlysine rich domain依存性にRatl細胞のコロニー形成能を増強することが確認された。t(11;19)転座により形成されるMLL/MENは転写伸長因子の異常機能亢進により幹細胞腫瘍を白血化させる可能性があると考えられた。

Report

(1 results)
  • 1996 Annual Research Report

Research Products

(12 results)

All Other

All Publications (12 results)

  • [Publications] Kurokawa M: "Overexpression of the human AML1b proto-oncoprotein leads to neoplastic transformation of NIH3T3 cells." Oncogene. 12. 883-892 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sasaki K: "TPO/c-MPL ligand induces tyrosine phosphorylation of multiple cellular proteins including proto-oncogene products,VAV and c-CBL,and RAS signaling molecules." Biochem.Biophys.Res.Commun.216. 338-347 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamagata T: "A novel interferon regulatory factor family transcription factor,ICSAT/Pip/LSIRF,that negatively regulates the activity of interferon-regulated genes." Mol.Cell.Biol.16. 1283-1294 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tanaka T: "The extracellular signal-regulated kinase pathway phosphorylates AML1,an acute myeloid leukemia gene product,and potentially regulates its transactivation ability." Mol.Cell.Biol.16. 3967-3979 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ogawa S: "Structurally altered Evi-1 prorein generated in the 3q26q21 syndrome." Oncogene. 13. 183-191 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kurokawa M: "A conserved cystein residue in the runt homology domain of AML1 is required for the DNA binding ability and the transforming activity on fibroblasts." J.Biol.Chem.271. 16870-16876 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamagata T: "Eleveted plated count features the variant type of BCR/ABL junction in chronic myelogenous leukaemia." Br.J.Haematol.94. 370-372 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] MITANI K: "Chromosomal abnormalities and oncogenes." Int.J.Hematol.63. 81-93 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ogawa S: "Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia." Leukemia. 10. 788-794 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirai H: "cell cycle regulator genes in human leukemias." Proceedings of The First Fukuoka International Symposium on Medical Science:An approach to disease.131-141 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirai H: "Recent progress in molecular mechanisms of leukemogenesis:The cyclin-dependent kinase 4-inhibitor gene in human leukemias." Proceedings of The XVIII Symposium of the International Association for Comparative Research on Leukemia and Related Disease.(in press). (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ueno H: "Growth and survival signals transmitted via two distinct NPXY motifs within leukocyte tyrosine kinase,an insulin receptor-related tyrosine kinase." J.Biol.Chem.271. 27707-27714 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-03-31   Modified: 2016-04-21  

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