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

包括11q23在内的染色体易位与多种血液系统恶性肿瘤有关，包括新生婴儿和成人急性髓系白血病、淋巴细胞性白血病或双表型白血病，以及继发性急性髓系白血病，尤其是由拓扑异构酶II抑制药物诱导的继发性急性髓系白血病。克隆了婴幼儿急性白血病的t(4；11)(q21；q23)和t(11；19)(q23；p13)断裂点，发现了一个位于11q23的新基因MLL。MLL与参与身体分割的果蝇三胸有很强的同源性。MLL有两种DNA结合基序，AT挂钩和锌指，并作为转录因子发挥作用。涉及MLL的染色体易位导致融合mRNA的产生，融合mRNA由MLL基因的一部分和配对染色体上另一基因的一部分组成。婴幼儿…中急性单核细胞白血病细胞的染色体分析女性多表现为t(6；11)(q27；q23)易位。用位于染色体11q23的MLL基因的cDNA探针进行Southern杂交分析表明，该断裂点位于携带MLL基因第5-11外显子的8.3kb的BamHI片段上。Northern印迹分析显示一条与MLL嵌合转录本相对应的微弱条带。对一个携带重排的MLL基因的基因组克隆的结构分析表明，该断裂点位于MLL基因的第6和第7外显子之间，位于该区域的Alu序列中。通过原位染色体杂交和嵌合MLL基因克隆的核苷酸序列测定，证实融合到MLL 3的配对基因为位于染色体6q27上的AF6基因。结果表明，除MLL外显子6/AF6的主要嵌合克隆外，MLL的外显子5在一个克隆中与AF6融合。提示MLL/AF6基因外显子6在转录过程中发生剪接。在临床过程中，RT-PCR检测MLL/AF6基因外显子的数量与化疗无反应有关。较少

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