THE RELATION OF VARIANT MLL GENE TO CELL DEATH AND UNRESPONSIVENESS TO CHEMOTHERAPY IN INFANTILE LEUKEKEMIA WITH 11q23 TRANSLOCATION

11q23 易位婴儿白血病 MLL 基因变异与细胞死亡和化疗无反应的关系

• 批准号: 12670221
• 负责人: AKAO Yukihiro
• 金额: $ 2.18万
• 依托单位: INSTITUTE OF APPLIED BIOCHEMISTRY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670221/
• 关键词: INFANTILELEUKEMIA; CHROMOSOMAL TRANSLOCATION; MLLGENE; APOPTOSIS; DRUG RESISTENCE; CHIMERIC PROTEIN; 造血器腫瘍; 11q23; MILL遺伝子; MLL; 細胞増殖抑制; 亜ヒ酸

Chromosome translocations including 11q23 have been shown to be associated with a variety of hematopoietic malignancies, including de novo infant and adult acute myeloid, lymphoid, or biphenotypic leukemia, and secondary acute myeloid leukemias especially induced by topoisomerase II inhibitory drugs. Especially, the majority of infant acute leukemias show abnormalities of chromosome band 1 1q23.The breakpoints of t(4 ; 11)(q21 ; q23) and t(11 ; 19)(q23 ; p13) in infantile acute leukemia were cloned and a novel gene at 11q23 called MLL was identified. MLL shows a strong homology to the Drosophila trithorax, which is involved in body segmentation. MLL has two types of DNA binding motifs, AT hooks and zinc fingers, and acts as a transcriptional factor. Chromosome translocation involving MLL results in the production of fusion mRNA consisting of a part of the MLL gene and a part of another gene on the partner chromosome. Chromosomal analysis of acute monocytic leukemia cells in an infantil … More e female revealed a t(6 ; 11)(q27 ; q23) translocation. Southern blot analysis with a cDNA probe of the MLL gene on chromosome 11q23 indicated that the breakpoint was in a 8.3-kb BamHI fragment that carried exons 5-11 of MLL gene. Northern blot analysis showed a faint band corresponding to MLL chimeric transcript. Structual analysis of a genomic clone carrying the rearranged MLL gene, which originates from der(11) chromosome, demonstrated the breakpoint to be localized between exons 6 and 7 of the MLL gene and to lie in the Alu sequence of this region. The partner gene fusing to 3 of MLL was shown to be AF6 gene on chromosome 6q27 by in situ chromosome hybridization and nucleotide sequencing of chimeric MLL cDNA clones. However, it was shown that the exon 5 of MLL was fused to AF6 in a clone except major MLL exon 6/AF6 chimeric cDNA clones. These findings indicate that exon 6 of MLL is spliced out in the process of transcription in a variant MLL/AF6.In clinical course, the amount of variant MLL/AF6 evaluated by RT-PCR was associated with the unresponsiveness to chemotherapy. Less

包括11 q23在内的染色体易位已被证明与多种造血系统恶性肿瘤相关，包括新生婴儿和成人急性髓性、淋巴样或双表型白血病，以及继发性急性髓性白血病，尤其是由拓扑异构酶II抑制药物诱导的。特别是大多数婴儿急性白血病都表现为染色体11 q23带异常。克隆了婴儿急性白血病的t（4 ; 11）（q21 ; q23）和t（11 ; 19）（q23 ; p13）断裂点，并在11 q23处发现了一个新基因MLL。MLL显示出与果蝇三胸的强烈同源性，其参与身体分割。MLL具有两种类型的DNA结合基序，AT钩和锌指，并作为转录因子。涉及MLL的染色体易位导致由MLL基因的一部分和伴侣染色体上的另一基因的一部分组成的融合mRNA的产生。急性单核细胞白血病细胞染色体分析 ...更多信息 1例女性为t（6 ; 11）（q27 ; q23）易位。用11 q23上的MLL基因cDNA探针进行Southern杂交分析，发现断裂点位于MLL基因外显子5-11的8.3kb的BamHI片段上。北方印迹分析显示一条对应于MLL嵌合转录本的微弱条带。对来自der（11）染色体的携带重排MLL基因的基因组克隆的结构分析表明，断裂点位于MLL基因的外显子6和7之间，并且位于该区域的Alu序列中。通过染色体原位杂交和核苷酸序列测定，证实与MLL 3融合的伴侣基因是位于染色体6 q27上的AF 6基因。然而，除了主要的MLL外显子6/AF 6嵌合cDNA克隆外，MLL的外显子5在克隆中与AF 6融合。这些结果表明，MLL基因第6外显子在转录过程中发生剪接，形成MLL/AF 6变异体。在临床过程中，RT-PCR检测的MLL/AF 6变异体的数量与化疗无反应性相关。少

项目成果

Kitamura K, Minami Y, Yamamoto K, Akao Y, Kiyoi H, and Naoe T.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis."Leukemia. 14. 1743-1750 (2000)

Kitamura K、Minami Y、Yamamoto K、Akao Y、Kiyoi H 和 Naoe T.：“三氧化二砷诱导的细胞凋亡中 CD95 独立的 caspase 8 激活的参与。”白血病。

Akao, Y. and Nakagawa Y.: "Arsenic-induced apoptosis in malignant cells"in vitro. Leukemia and Lymphoma. 37. 53-63 (2000)

Akao, Y. 和 Nakakawa Y.：“砷在体外诱导恶性细胞凋亡”。

Akao Y, and Isobe M.: "Molecular analysis of the rearranged genome and chimeric mRNAs caused by the t'6 : 11)(q27 ; q23) chromosome translocation involving MLL in an infant acute monocytic leukemia"Genes Chromosomes Cancer. 27. 412-417 (2000)

Akao Y 和 Isobe M.：“对婴儿急性单核细胞白血病中涉及 MLL 的 t6 : 11)(q27;q23) 染色体易位引起的重排基因组和嵌合 mRNA 的分子分析”基因染色体癌症。

Akao Y, Nakagawa Y.: "Arsenic-induced apoptosis in malignant cells in vitro"Leukemia and Lymphoina. 37. 53-63 (2000)

Akao Y，Nakakawa Y.：“体外砷诱导恶性细胞凋亡”白血病和淋巴细胞。

Kitamura K, Minami Y, Yamamoto K, Akao Y, Kiyoi H, Naoe T.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis"Leukemia. 14. 1743-1750 (2000)

Kitamura K、Minami Y、Yamamoto K、Akao Y、Kiyoi H、Naoe T.：“三氧化二砷诱导的细胞凋亡中 CD95 独立的 caspase 8 激活的参与”白血病。