Yu B D, Hess J L, Horning S E, Brown G A, Korsmeyer S J
Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature. 1995 Nov 30;378(6556):505-8. doi: 10.1038/378505a0.
The mixed-lineage leukaemia gene (MLL/HRX/ALL-1) is disrupted by chromosomal translocation in human acute leukaemias that often display mixed lymphoid-myeloid phenotypes and present in infancy. MLL possesses a highly conserved SET domain also found in Drosophila trithorax (trx) and Polycomb group (Pc-G) genes, which are known to regulate homeotic genes (HOM-C) in a positive or negative fashion, respectively. Mll was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its role in pattern development. Mll heterozygous (+/-) mice had retarded growth, displayed haematopoietic abnormalities, and demonstrated bidirectional homeotic transformations of the axial skeleton as well as sternal malformations. Mll deficiency (-/-) was embryonic lethal. Anterior boundaries of Hoxa-7 and Hoxc-9 expression were shifted posteriorly in Mll +/- embryos, but their expression was abolished in Mll -/- embryos. Thus Mll is required for proper segment identity in mammals, displays haplo-insufficiency, and positively regulates Hox gene expression.
混合谱系白血病基因（MLL/HRX/ALL-1）在人类急性白血病中因染色体易位而被破坏，这些白血病通常表现出混合的淋巴样-髓样表型，且在婴儿期出现。MLL拥有一个高度保守的SET结构域，果蝇的三胸节基因（trx）和多梳蛋白家族（Pc-G）基因中也存在该结构域，已知它们分别以正向或负向方式调节同源异型基因（HOM-C）。通过胚胎干细胞中的同源重组在小鼠中靶向Mll，以评估其在模式发育中的作用。Mll杂合子（+/-）小鼠生长迟缓，表现出造血异常，并显示出轴向骨骼的双向同源异型转化以及胸骨畸形。Mll缺陷（-/-）在胚胎期致死。在Mll +/-胚胎中，Hoxa-7和Hoxc-9表达的前边界向后移动，但在Mll -/-胚胎中它们的表达被消除。因此，Mll是哺乳动物中正确节段身份所必需的，表现出单倍剂量不足，并正向调节Hox基因表达。
