Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy‐related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL‐CBP expression and to assess the immediate effects of induced MLL‐CBP expression on hematopoiesis. Within days of activating MLL‐CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self‐renewal/proliferation. MLL‐CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL‐CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal γ‐irradiation or N‐ethyl‐N‐nitrosourea (ENU), MLL‐CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy‐induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL‐CBP therapy‐related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.