V-MYC IN A SIMPLE, SINGLE-GENE RETROVIRAL VECTOR CAUSES RAPID INDUCTION OF LEUKEMIA AND CONCOMITANT APOPTOSIS FOLLOWING BONE-MARROW TRANSPLANTATION

We have previously developed an in vivo model of leukemogenesis utiliz ing mice reconstituted with genetically modified bone marrow cells. Ba sed on those studies, a new single gene retroviral vector has been eng ineered which efficiently transfers v-myc into immature murine bone ma rrow cells. All reconstituted mice developed leukemia with a short lat ency period (5-11 weeks). In addition to hyperproliferation associated with elevated levels of PCNA, extensive apoptosis was also observed i n all leukemic animals with p53 accumulating in the apoptotic cells. W hereas bar encoded protein, an effector of p53 apoptotic activity was detected in apoptotic cells, p21(Waf1) protein, a potential mediator o f p53 growth suppression was not detected in these cells suggesting th at v-myc-induced apoptosis was independent of the ability of p53 to in duce p21(Waf1). These results indicate that apoptosis, a part of the c ellular response to v-myc expression, does not prevent leukemia develo pment and that hyperproliferation rather than abrogation of oncogene-i nduced apoptosis appears to be a critical event in v-myc-induced leuke mia.