The gene encoding c-ABL, a nonreceptor protein tyrosine kinase, is involved in a chromosomal translocation resulting in expression of a BCR-Abl fusion protein that causes most chronic myelogenous and some acute lymphocytic leukemias (CML and ALL) in humans. The Abelson murine leukemia virus (A-MuLV) expresses an alternative form of c-Abl, v-Abl, that transforms murine pro-B cells, resulting in acute leukemia and providing an experimental model for human disease. Gleevec (STI571) inhibits the Abl kinase and has shown great utility against CML and ALL in humans, although its usefulness is limited by acquired resistance. Since STI571 is active against A-MuLV-transformed cells in vitro, we performed a retroviral cDNA library screen for genes that confer resistance to apoptosis induced by STI571. We found that forced expression of Cdk6 promotes continued cell division and decreased apoptosis of leukemic cells. We then determined that the transcription factor E2A negatively regulates Cdk6 transcription in leukemic pro-B cells and that the v-Abl kinase stimulates Cdk6 expression via an extracellular signal-regulated kinase 1-dependent pathway. Finally, we show that the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor PD0332991 can act synergistically with STI571 to enhance leukemic cell death, suggesting a potential role for CDK6 inhibitors in the treatment of STI571-resistant CML or ALL.