CREB is a leucine zipper transcription factor that controls cell proliferation, differentiation, and survival. CREB is overexpressed in bone marrow cells from the majority of patients with acute lymphoblastic and myeloid leukemia. CREB transgenic mice develop myeloproliferative disease, i.e. preleukemia, but not acute leukemia. Therefore, CREB is an oncogene that requires additional mutations. We are studying other cooperating oncogenes that contribute to leukemogenesis. In addition, downstream target genes are being explored.