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Hematopoietic stem and progenitor cells (HSPCs) are necessary for life‐long blood production and replenishment of the hematopoietic system during stress. We recently reported that nuclear factor I/X ( Nfix)  promotes HSPC survival post‐transplant. Here, we report that ectopic expression of  Nfix  in primary mouse HSPCs extends their ex vivo culture from about 20 to 40 days. HSPCs overexpressing  Nfix  display hypersensitivity to supportive cytokines and reduced apoptosis when subjected to cytokine deprivation relative to controls. Ectopic  Nfix  resulted in elevated levels of  c‐Mpl  transcripts and cell surface protein on primary murine HSPCs as well as increased phosphorylation of STAT5, which is known to be activated down‐stream of c‐MPL. Blocking c‐MPL signaling by removal of thrombopoietin or addition of a c‐MPL neutralizing antibody negated the antiapoptotic effect of  Nfix  overexpression on cultured HSPCs. Furthermore, NFIX was capable of binding to and transcriptionally activating a proximal  c‐Mpl  promoter fragment. In sum, these data suggest that NFIX‐mediated upregulation of  c‐Mpl  transcription can protect primitive hematopoietic cells from stress ex vivo. S tem  C ells   2018;36:943–950

Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c‐Mpl