The Inhibitor of MyoD Family A Promotes Terminal Myeloid Differentiation

Abstract The differentiation of hematopoietic stem and progenitor cells is tightly regulated to maintain immune and blood homeostasis while also responding to injury and immunological insult. Myeloid lineage-committed progenitor cells are highly proliferative, but do not self-renew and must be continually replenished by the differentiation of hematopoietic stem cells. The process of terminal differentiation is controlled by various cell-intrinsic and - extrinsic factors, and the interactions between these factors remain not well understood. We hypothesize that the Inhibitor of MyoD Family A (I-mfa) protein is a novel regulator of myeloid lineage differentiation through its interaction with other cell-intrinsic factors. To examine this, mice which lack I-mfa expression (I-mfanull) were compared to wild type (WT) 129Sv age- and sex-matched controls. I-mfanull animals had reduced spleen size (both in weight and total cellularity), but had preserved relative proportions of B, T, and myeloid cells as analyzed by flow cytometry when compared to WT. Analysis of the bone marrow (BM) myeloid lineage-committed progenitors showed an accumulation of common myeloid progenitors (CMP) and granulocyte-macrophage progenitors (GMP) in I-mfanull animals when compared to WT. In serial colony forming unit assays I-mfanull BM produced fewer mature colonies and continued to produce colonies after 5 passages, suggesting aberrant self-renewal. Using myeloid cell lines lacking or overexpressing I-mfa, the molecular mechanism by which I-mfa acts is being elucidated. These results taken together suggest I-mfa acts to promote differentiation of myeloid cells, an effect which may be important in the treatment of myeloid neoplasms or bone marrow failure.