Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs

Tomoya Muto, Callum S. Walker, Kwangmin Choi, Kathleen Hueneman, Molly A. Smith, Zartash Gul, Guillermo Garcia-Manero, Averil Ma, Yi Zheng, Daniel T. Starczynowski

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.

Original languageEnglish (US)
Pages (from-to)535-545
Number of pages11
JournalNature Immunology
Volume21
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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