Molecular Diagnosis of Human Leukemias

人类白血病的分子诊断

• 批准号: 04253208
• 负责人: HIRAI Hisamaru
• 金额: $ 12.16万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04253208/
• 关键词: t(3 ; 21) translocation; chronic myelocytic leukemia; blastic crisis; AML1; EVI-1 chimeric gene; AML1 gene; EVI-1 gene; transcription factor; N-ras遺伝子; p53遺伝子; Ph^1陽性ALL; CML急性転化; 骨髄異形成症候群; 白血病; SSCP法; PCR法

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.

T(3；21)(q26；q22)易位被认为是慢性粒细胞白血病(CML)急变的诱因。这种相互易位产生一个AML1/EVI-1嵌合基因，它被转录为融合mRNAs。180kD的AML1/EVI-1融合蛋白含有AML1的一半氨基末端，含有一个与整个锌指EVI-1蛋白融合的矮小同源结构域。AML1/EVI-1融合转录本在所有三例接受检查的t(3；21)携带者白血病中都是一致的。合成与包括正品AML1和EVI-1转录起始序列的序列互补的反义寡核苷酸，特异性地抑制t(3；21)易位的白血病细胞的生长。这些发现强烈表明t(3；21)易位导致形成一类新的嵌合转录因子，该因子可能通过干扰细胞的生长和分化而促进白血病的进展。

项目成果

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)

Hanazono Y、Chiba S、Sasaki K、Mano H、Miyajima A、Arai K、Yazaki Y、Hirai H：“c-fps/fes 蛋白酪氨酸激酶与粒细胞巨噬细胞集落刺激因子触发的信号通路有关，并且

Sugimoto K: "Mutations of the p53 gene in myelodysplastic syndromes and MDS-derived leukemia." Blood. 81. 3022-3026 (1993)

Sugimoto K：“骨髓增生异常综合征和 MDS 衍生性白血病中的 p53 基因突变。”

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

Okawa S、Mitani K、Sato Y、Sugimoto K、Toyoshima H、Mano H、Takaku F、Yazaki Y、Hirai H：“检测急性早幼粒细胞白血病中的 PML/RARα 融合基因，涉及染色体 15,17 的复杂易位，

Sasaki K et al.: "Coordinate expression of the α and β chains of human gramulocyte-macrophage colony-stimulating factor receptor confers ligand-induced morphological transformation in mouse fibroblases." J.Biol.Chem.(In press).

Sasaki K 等人：“人粒细胞巨噬细胞集落刺激因子受体的 α 和 β 链的协调表达在小鼠成纤维细胞中赋予配体诱导的形态转化。”（正在出版）。

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)

Toyoshima H：“人类 ltk 受体酪氨酸激酶的不同剪接 cDNA 可以预测具有或不具有酪氨酸激酶结构域和可溶性受体蛋白的受体蛋白。”