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The molecular mechanisms governing the transition from hematopoietic stem cells (HSCs) to lineage-committed progenitors remain poorly understood. Transcription factors (TFs) are powerful cell intrinsic regulators of differentiation and lineage commitment, while cytokine signaling has been shown to instruct the fate of progenitor cells. However, the direct regulation of differentiation-inducing hematopoietic TFs by cell extrinsic signals remains surprisingly difficult to establish. PU.1 is a master regulator of hematopoiesis and promotes myeloid differentiation. Here we report that tumor necrosis factor (TNF) can directly and rapidly upregulate PU.1 protein in HSCs in vitro and in vivo. We demonstrate that in vivo, niche-derived TNF is the principal PU.1 inducing signal in HSCs and is both sufficient and required to relay signals from inflammatory challenges to HSCs.

Original publication

DOI

10.1182/blood-2018-02-832998

Type

Journal article

Journal

Blood

Publication Date

21/02/2019

Volume

133

Pages

816 - 819

Keywords

Animals, Cell Differentiation, Hematopoietic Stem Cells, Inflammation, Mice, Myelopoiesis, Proto-Oncogene Proteins, Signal Transduction, Stem Cell Niche, Trans-Activators, Tumor Necrosis Factor-alpha