Studies have focused on two genetic loci, c-myb and Mml1, whose activation by retroviral insertional mutagenesis contribute to promonocytic leukemia in our acute monocytic leukemia (AMoL) model. Analysis of some recently discovered tumors with integrations at the distal 3' end of c-myb, delineated a new mechanism of activation of this proto-oncogene which apparently involve both enhancer insertion and carboxyl terminal truncation. The 38 aa truncation c-Myb in such leukemias is unique because all carboxyl terminal activating truncations previously described have involved removal of at least 240 aa. In trying to understand the affects of members of the Myb family on differentiation, proliferation, and apoptosis, as well as consequences on Myb of protein truncation, we have moved our attention to in vitro studies. Results demonstrate that c-myb inhibits both granulocyte and macrophage differentation pathways only at late stages and not early stages of differentiation, and maintains the proliferative state of cells. Furthermore, no differences were observed in doubling times or in the morphology of cells when truncated versions of c-Myb were compared to full length c-Myb. B-Myb was shown to accelerate apoptosis in TGFbeta-treated M1 myeloid progenitor cells. A new common site of proviral insertion in the promonocytic leukemias has been identified. Chromosomal mapping studies, have determined that Mml1 is located on the proximal end of mouse chromsome 10. Experiments are aimed at searching for a new proto-oncogene in the vicinity of the proviral insertions.
