Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: Potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia

Hoxa9 and Meis1a are homeodomain transcription factors that heterodimerize on DNA and are down-regulated during normal myeloid differentiation. Hoxa9 and Meis1a cooperate to induce acute myeloid leukemia (AML) in mice, and ar e coexpressed in human AML. Despite their cooperativity in leukemogenesis, we demonstrated previously that retroviral expression of Hoxa9 alone-in the absence of coexpressed retroviral Meis1 or of expression of endogenous Mei s genes-blocks neutrophil and macrophage differentiation of primary myeloid progenitors cultured in granulocyte-macrophage colony-stimulating factor ( GM-CSF). Expression of Meis1 alone did not immortalize any factor-dependent marrow progenitor. Because HoxA9-immortalized progenitors still execute gr anulocytic differentiation in response to granulocyte CSF (G-CSF) and monoc yte differentiation in response to macrophage CSF (M-CSF), we tested the po ssibility that Meis1a cooperates with Hoxa9 by blocking viable differentiat ion pathways unaffected by Hoxa9 alone. Here we report that Meis1a suppress es G-CSF-induced granulocytic differentiation of Hoxa9-immortalized progeni tors, permitting indefinite self-renewal in G-CSF. Meis1a also reprograms H oxa9-immortalized progenitors to proliferate, rather than die, in response to stem cell factor (SCF) alone. We propose that Meis1a and Hoxa9 are part of a molecular switch that regulates progenitor abundance by suppressing di fferentiation and maintaining self-renewal in response to different subsets of cytokines during myelopoiesis. The independent differentiation pathways targeted by Hoxa9 and Meis1a prompt a "cooperative differentiation arrest" hypothesis for a subset of leukemia, in which cooperating transcription fa ctor oncoproteins block complementary subsets of differentiation pathways, establishing a more complete differentiation block in vivo.