Ski is a corepressor protein originally identified as a retrovirally transduced oncoprotein. Genetic deletion of Ski has revealed essential roles in multiple developmental processes. Suggestion that Ski may play a role in hematopoiesis first came from expression of v-Ski and c-Kit, which induced the continuous in vitro growth of primary avian multipotent progenitors. However, the hematopoietic phenotype of Ski−/− mice has not been described. Here, we show that Ski loss of function results in loss of hematopoietic stem cell (HSC) fitness and abnormal regulation of myeloid progenitor numbers. Fetal liver Ski−/− HSC engraft well in ablated recipients, but are not competitive in engraftment. Moreover, Ski null embryonic stem cells generate many tissues in chimeras, but infrequently participate in hematopoiesis. Thus, Ski null HSC are not competitive in both transplant and chimera settings, indicating a defect in stem cell fitness. Engrafted Ski−/− fetal liver cells generate fewer myeloid lineage cells than wild type littermates, and accumulate granulocytemonocyte progenitors. Growth factor independent -1 (Gfi1) is a transcriptional repressor that controls HSC maintenance and myeloid progenitor differentiation. Gfi1−/− and Ski−/− hematopoietic stem and myeloid progenitor phenotypes are strikingly similar. We find that Ski functions as a corepressor for Gfi1. Both endogenous and synthetic Gfi1 and Ski physically interact in vitro and upon Gfi1 target genes. Knockdown of Gfi1 or Ski results in derepression of these targets. Thus, our results provide a molecular link between the similar HSC and myeloid progenitor phenotypes engendered by Gfi1 or Ski deletion.

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