Our laboratory is interested in the transcriptional regulation of normal blood cell development and leukemia. All blood cells arise from a small population of hematopoietic stem cells (HSCs) that have the capacity to, both, self-renew and mature stepwise into all known blood lineages. HSCs are also the ancestors of leukemic cells. As HSCs mature, they undergo successive changes in gene expression that are orchestrated by transcription factors. The transcriptional apparatus must ensure that genes specific to immature cells are repressed as differentiation proceeds while genes necessary for the function of mature blood cells become activated. This is achieved by co-operative action of a variety of lineage specific and general transcription factors. Individual transcription factors function in a highly context sensitive manner, so that in some cases the same transcription factor may even have opposite roles in different lineages. Using genetically engineered mouse strains, we investigate how key transcription factors establish differentiation specific transcriptional programs and how abnormal transcription factors derail this process to allow for the development leukemia. Our major emphasis is on three transcription factors: the Ets-related transcription factor Tel/Etv6 and the zinc-finger transcription factor Gfi-1, both critical for maintaining HSCs in the bone marrow, and the leukemia translocation-associated hybrid transcription factor Tel-Aml1.