Citation/Abstract

Leukemia results from the accumulation of multiple genetic alterations that disrupt the control mechanisms of normal growth and differentiation of hematopoietic cells. The use of inbred mouse strains that develop leukemia has greatly facilitated the identification of genes that contribute to the neoplastic transformation of hematopoietic cells. BXH-2 mice develop myeloid leukemia due to the expression of an ecotropic Murine Leukemia Virus that acts as an insertional mutagen to alter the expression of cellular protooncogenes. We report the isolation of a novel locus, Meis1, that serves as a site of viral integration in 15% of the tumors arising in BXH-2 mice. Northern (RNA) blot analysis demonstrated that a Meis1 probe detected a 3.8-kb mRNA present in all BXH-2 tumors, whereas tumors containing integrations at the Meis1 locus expressed an additional truncated transcript. Analysis of a Meis1 cDNA clone demonstrated that it was a novel member of the homeobox containing family of transcription factors. Using a binding selection technique we demonstrate that Meis1 is capable of binding DNA in a sequence specific manner. The homeodomain of Meis1 is most closely related to the PBX/exd family of homeobox proteins, suggesting that Meis1 functions in a similar fashion by cooperative binding to a distinct subset of HOX proteins. Collectively, these results indicate that altered expression of the DNA binding protein Meis1 may be one of the events that lead to tumor formation in BXH-2 mice.