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Significance Inflammation degrades hematopoietic stem and progenitor (HSPC) function, leading to myeloid-skewing and bone marrow failure. We show that the transcriptional regulator STAT3 has an intrinsic protective role in the hematopoietic system, which is necessary to preserve HSPCs and lineage-balanced hematopoiesis. We find that concomitant removal ofUbe2n , encoding the proinflammatory signal transducer Ubc13, mitigates hematopoietic failure, myeloid overproduction, and a majority of transcriptional deregulation withinStat3 -null HSPCs. These data imply an epistatic relationship betweenStat3 andUbe2n , and suggest that STAT3 protects the hematopoietic system from the effects of excessive proinflammatory signaling by restraining Ubc13.

Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis