COOPERATIVE ACTIVATION OF HOXA AND PBX1-RELATED GENES IN MURINE MYELOID LEUKEMIAS

Retroviruses induce myeloid leukaemia in BXH-2 mice by the insertional mutation of cellular proto-oncogenes or tumour suppressor genes. Dise ase genes can thus be identified by proviral tagging through the ident ification of common viral integration sites in BXH-2 leukaemia. Here, we describe a new approach for proviral tagging that greatly facilitat es the identification of BXH-2 leukaemia genes. Using this approach, w e identify three genes whose expression is activated by proviral integ ration in BXH-2 leukaemias; Hoxa7, Hoxa9, and a Pbx1-related homeobox gene, Meis1. Proviral activation of Hoxa7 or Hoxa9 is strongly correla ted with proviral activation of Meis1 implying that Hoxa7 and Hoxa9 co operate with Meis1 in leukaemia formation. These studies provide the f irst genetic evidence that Pbx1-related genes cooperate with Hox genes in leukaemia formation and identify a number of new murine myeloid le ukaemia genes.