MZF1 is a transcription factor belonging to the Krüppel family of zinc finger proteins, expressed in totipotent hemopoietic cells as well as in myeloid progenitors. Here we have inactivated Mzfi1 by gene targeting. Mzf1(-/-) mice develop lethal neoplasias characterized by the infiltration and complete disruption of the liver architecture by a monomorphic population of cells of myeloid origin reminiscent of human chloromas. Mzf1 inactivation results in a striking increase of the autonomous cell proliferation and of the ability of Mzf1(-/-) hemopoietic progenitors to sustain long-term hemopoiesis. These findings demonstrate that Mzf1 can act as a tumor/growth suppressor in the hemopoietic compartment.