IFN Consensus Sequence Binding Protein/IFN Regulatory Factor-8 Guides Bone Marrow Progenitor Cells Toward the Macrophage Lineage

IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in myeloid cell development, lineage marker-negative (Lin(-)) bone marrow progenitor cells were purified from ICSBP(+/+) and ICSBP(-/-) mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin(-) progenitor cells, and its levels were markedly increased by IFN-gamma. The colony-forming potential of ICSBP(-/-) progenitor cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-gamma inhibited colony formation, while promoting macrophage maturation in ICSBP(+/+) cells. In contrast, the effects of IFN-gamma were completely absent in ICSBP(-/-) progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in -/- progenitor cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in myeloid cell development by controlling lineage selection and is indispensable for IFN-gamma-dependent modulation of progenitor cell maturation.