Myeloid leukemia: Disease genes and mouse models

The BXH2 inbred mouse strain represents a very useful model system for the study of human myeloid leukemia. Not only do these mice have the highest spontaneous incidence of myeloid leukemia of any known inbred mouse strain (>95%), but the leukemias are retro vira lly-induced and the pro viral integration sites in the tumors can thus be used as insertional tags to identify the disease genes. Using this proviral tagging approach, our laboratory has identified five genes that appear to be important causative agents of BXH2 myeloid leukemia. These genes include a tumor suppressor gene (N/7), a proto-oncogene (Myb), two Hox genes (Hoxa? and Hoxa9) and a /Vue/-related hoineobox gene (Afeisl). Interestingly, two out of the five genes (NF1 and BOXA9) have also be shown to be causally-associated with human myeloid leukemia. In my presentation I will (1) summarize what we know about the role of these five BXH2 disease genes in myeloid disease and described how we are using this information to develop new mouse models of human myeloid leukemia, (2) outline some of our more current research which has important implications for understanding how homeobox genes function in both normal development and in myeloid disease, and (3) describe a new inverse PCR/DNA sequence-based approach for identifying BXH2 disease genes that has revolutionized the way we use proviral tagging to identify disease genes. Finally, I will describe some of the many new unpublished BXH2 disease genes we have recently identified by this inverse PCR/DNA.