Molecular Diagnosis of Human Leukemias

1993 Fiscal Year Final Research Report Summary

• Project/Area Number: 04253208
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: University of Tokyo
• Principal Investigator: HIRAI Hisamaru University of Tokyo, 3rd Dept.of Internal Med., Lecturer, 医学部(病), 講師 (90181130)
• Co-Investigator(Kenkyū-buntansha): OGAWA Seishi University of Tokyo, 3rd Dept.of Internal Med., Medical Fellow, 医学部(病), 医員 ; MITANI Kinuko University of Tokyo, 3rd Dept.of Internal Med., Assistant Pro., 医学部(病), 助手 (50251244)
• Project Period (FY): 1992 – 1993
• Keywords: t(3 ; 21) translocation / chronic myelocytic leukemia / blastic crisis / AML1 / EVI-1 chimeric gene / AML1 gene / EVI-1 gene / transcription factor

Research Abstract

The t(3 ; 21)(q26 ; q22) translocation is thought to trigger blastic crisis in chronic myelocytic leukemia (CML). This reciprocal translocation generates an AML1/EVI-1 chimeric gene which is transcribed as fusion mRNAs. The 180 kD AML1/EVI-1 fusion protein contains an amino-terminal half of AML1 including a runt homology domain which is fused to the entire of zinc finger EVI-1 protein. The AML1/EVI-1 fusion transcript is consistent among all three cases of the t(3 ; 21)-carrying leukemia examined. Synthetic antisense oligonucleotides complementary to the sequences including the transcriptional initiation sequences of authentic AML1 and EVI-1 specifically suppress growth of leukemia cells with the t(3 ; 21) translocation. These findings strongly suggest that the t(3 ; 21) translocation results in the formation of a new class of a chimeric transcription factor which could contribute to leukemic progression through interference with cell growth and differentiation.

Research Products

• [Publications] Toyoshima H: "Differently spliced cDNAs of human ltk receptor tyrosine kinase predeict receptor proteins with and without tyrosine kinase domain and a soluble receptor protein." Proc.Natl.Acad.Sci.USA. 90. 5404-5408 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sugimoto K: "Mutations of the p53 gene in myelodysplastic syndromes and MDS-derived leukemia." Blood. 81. 3022-3026 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hanazono Y: "c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3." EMBO J.12. 1641-1646 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ogawa S: "Detection of the PML/RAR α fusion gene in acute promyelocytic leukemia with a complex translocation involving chromosome 15,17,and 18." Cancer Genet.Cytogenet.69. 113-117 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Amano M: "Rearrangement of retinoic acid receptor α and PML in promyelocytic blast crisis of Ph1 chromosome positive chronic myelocytie leukemia with normal copies of chromosome 15." Blood. 81. 2469-2470 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Mitani K: "Generation of the AML1/Evi-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia."
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Toyoshima H,Kozutsumi H,Maru Y,Hagiwara K,Furuya A,Mioh H,Hanai N,Takaku F,Yazaki Y,Hirai H: "Differently spliced cDNAs of human 1tk receptor tyrosine kinase predict receptor proteins with and without tyrosine kinase domain and a soluble receptor protein" Proc.Natl.Acad.Sci.USA. 90. 5404-5408 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sugimoto K,Hirano N,Toyoshima H,Chiba S,Mano H,Takaku F,Yazaki Y,Hirai H: "Mutations of the p53 gene in myelodysplastic syndromes and MDS-derived leukemia" Blood. 81. 3022-3026 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hanazono Y,Chiba S,Sasaki K,Mano H,Miyajima A,Arai K,Yazaki Y,Hirai H: "c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3" EMBO J.12. 1641-1646 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hanazono Y,Chiba S,Sasaki K,Mano H,Yazaki Y,Hirai H: "Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells" Blood. 81. 3193-3196 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sasaki K,Chiba S,Hanazono Y,Mano H,Yazaki Y,Hirai H: "Coordinate expression of the alpha and beta chains of human granolocyte-macrophage colony-stimulating factor receptor confers ligand-induced morphological transformation in mouse fibroblasts" J.Biol.Chem.268. 13697-13702 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ogawa S,Mitani K,Sato Y,Sugimoto K,Toyoshima H,Mano H,Takaku F,Yazaki Y,Hirai H: "Detection of the PML/RARalpha fusion gene in acute promyelocytic leukemia with a complex translocation involving chromosome 15,17, and 18" Cancer Genet.Cytogenet.69. 113-117 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Amano M,Togawa A,Tsurugano S,Soda Y,Yuo A,Takaku F,Ogawa S,Hirai H,Yamada K: "Rearrangement of retinoic acid receptor alpha and PML in promyelocytic blast crisis of Phl chromosome positive chronic myelocytic leukemia with normal copies of chromosome 15" Blood. 81. 2469-2470 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Mitani K,Ogawa S,Miyoshi H,Kurokawa M,Mano H,Yazaki Y,Ohki M,Hirai H: "Generation of the AML1/Evi-1 fusion gene in the t(3 ; 21)(q26 ; q22) causes blastic crisis in chronic myelocytic leukemia" EMBO. (in press).
  • Description: 「研究成果報告書概要(欧文)」より