ALTERED HOX EXPRESSION AND SEGMENTAL IDENTITY IN MLL-MUTANT MICE

THE mixed-lineage leukaemia gene (MLL/HRX/ALL-1) is disrupted by chrom osomal translocation in human acute leukaemias that often display mixe d lymphoid-myeloid phenotypes and present in infancy(1-4). MLL possess es a highly conserved SET domain also found in Drosophila trithorax (t rx) and Polycomb group (Pc-G) genes, which are known to regulate homeo tic genes (HOM-C) in a positive or negative fashion, respectively(5). Mll was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its role in pattern development. MII heterozygou s (+/-) mice had retarded growth, displayed haematopoietic abnormaliti es, and demonstrated bidirectional homeotic transformations of the axi al skeleton as well as sternal malformations. Mll deficiency (-/-) was embryonic lethal. Anterior boundaries of Hoxa-7 and Noxc-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 reg ulates Hox gene expression.