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

包括11q23在内的染色体易位已被证明与多种造血恶性肿瘤有关，包括新生儿和成人急性髓性、淋巴性或双表型白血病，以及继发性急性髓性白血病，特别是由拓扑异构酶II抑制药物引起的白血病。特别是，大多数婴儿急性白血病表现为染色体1 1q23带异常。克隆了婴儿急性白血病中t(4; 11)（q21; q23）和t(11; 19)（q23; p13）的断点，并在11q23位点鉴定出一个新的基因MLL。MLL与果蝇三胸有很强的同源性，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的染色体易位导致融合mRNA的产生，融合mRNA由MLL基因的一部分和伴侣染色体上另一个基因的一部分组成。对1例婴幼儿急性单核细胞白血病细胞的染色体分析，发现有t(6; 11)（q27; q23）易位。对11q23染色体上MLL基因的cDNA探针进行Southern blot分析，发现断点在一个8.3 kb的BamHI片段上，该片段携带MLL基因的外显子5-11。Northern blot分析显示一个微弱的条带对应于MLL嵌合转录物。对一个携带重排MLL基因的基因组克隆的结构分析表明，该突变点位于MLL基因的外显子6和7之间，位于该区域的Alu序列。通过原位杂交和嵌合MLL cDNA克隆的核苷酸测序，发现MLL的3号融合的伴侣基因为6q27号染色体上的AF6基因。结果表明，除了MLL的外显子6/AF6嵌合克隆外，MLL的外显子5在一个克隆中与AF6融合。这些发现表明，在MLL/AF6突变体的转录过程中，MLL的外显子6被剪切掉。在临床过程中，RT-PCR评估的MLL/AF6变异量与化疗无反应相关。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