1996 Fiscal Year Annual Research Report

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 Institution	The 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)
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。

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)
[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)
[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)
[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)
[Publications] Ogawa S: "Structurally altered Evi-1 prorein generated in the 3q26q21 syndrome." Oncogene. 13. 183-191 (1996)
[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)
[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)
[Publications] MITANI K: "Chromosomal abnormalities and oncogenes." Int.J.Hematol.63. 81-93 (1996)
[Publications] Ogawa S: "Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia." Leukemia. 10. 788-794 (1996)
[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)
[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)
[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)

1996 Fiscal Year Annual Research Report

造血幹細胞腫瘍白血病化の分子機構の解析

Principal Investigator

三谷 絹子 東京大学, 医学部・附属病院, 助手 (50251244)

Research Products

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

[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)

[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)

[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)

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

[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)

[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)

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

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

[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)

[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)

[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)

三谷絹子東京大学, 医学部・附属病院, 助手 (50251244)