The laboratory has developed a murine model for acute myeloid leukemia and the primary objective has been to understand the mechanisms involved in the development of this disease. Since the leukemia is induced by a combination of retroviruses and pristane-induced inflammation, the major focus has been to determine the role of each of these contributing factors on oncogene activation, and on cellular transformation, expansion and trafficking. Our recent studies on c-myb activation have determined that the protooncogene can be activated by two viral-induced mechanisms in promonocytic leukemias which are different from those previously found. These were activations found in FB29-induced promonocytic leukemias having two new sites of integration. Of particular interest was the fact that the aberrant Myb protein expressed in one of these tumors has the smallest N- terminal truncation thus far determined for a leukemia-associated Myb. Another study aimed at understanding the temporal relationship of myb activation (using RT-PCR technology) to the development of disease determined that the myb protooncogene is activated very early in the disease process. Cells with this activation are most prevalent in the bone marrow at three weeks post-virus infection and disseminate during disease progression to other sites including the spleen, liver, and bone marrow. By 8 weeks, 100% of mice harbor cells that have undergone insertional mutagenesis, although it has been shown previously in numerous experiments that only approximately 50% of mice succumb to disease. Progress has also been made in the determination of viral genes specifically required for leukemia development. Analysis of recombinant viruses indicate specific roles for gag and env genes in development of promonocytic leukemia in BALB/c mice.
