Fas-deficient (Fas ^lpr/lpr) mice constitutively expressing Bcl-2 in myeloid cells by the hMRP8 promoter often develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic Fas ^lpr/lpr hMRP8bcl-2 animals form clonogenic blast colonies in vitro and can transfer disease to wild-type mice. In vitro ligation of Fas on Fas^+/+ hMRP8bcl-2 marrow cells depletes approximately 50% of myeloid progenitor activity, demonstrating that Bcl-2 can only partially block Fas-mediated death signals in myelomonocytic progenitors. In addition, Fas ^lpr/lpr marrow contains greatly increased numbers of myeloid colony-forming cells as compared to Fas^+/+ controls. Taken together, these data suggest that Fas has a novel role in the regulation of myelopoiesis and that Fas may act as a tumor suppressor to control leukemogenic transformation in myeloid progenitor cells.