Identifying genetic pathways that cooperate in leukemogenesis facilitates our understanding of the molecular mechanisms at play. Interferon consensus sequence-binding protein (ICSBP) is a tumor suppressor, whose downregulation cooperates with BCR-ABL and NUP98-TOP1 gene products to accelerate leukemia induction in mouse models. Similarly, Meis1 synergizes with HoxA9 or NUP98-HOX (but not NUP98-TOP1) fusion genes to promote the early onset of leukemia. To investigate whether Icsbp deficiency interacts with Meis1 or its family member Meis3, we transplanted Icsbp(-/-) bone marrow (BM) cells after transduction with Meis1 or Meis3 retroviral vectors. Here, we show that enforced expression of Meis1 or Meis3 in Icsbp(-/-) BM cells induces a fatal, invasive myeloproliferative disease. Secondary mutations, such as activation of Mn1, led to the progression to acute myeloid leukemia in a few mice. Interestingly, expression of endogenous Meis1 and Meis3 mRNAs was repressed in the granulocytic progenitor population of Icsbp(-/-) mice. These results reveal a novel collaboration between Icsbp deficiency and Meis1/Meis3 in the acceleration of chronic myeloid leukemia-like disease.