IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

Nat Immunol. 2025 Feb;26(2):200-214. doi: 10.1038/s41590-024-02063-w. Epub 2025 Jan 9.

Abstract

Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt-β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an '18-gene signature' of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α-XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.

MeSH terms

  • Animals
  • Endoribonucleases* / genetics
  • Endoribonucleases* / metabolism
  • Gene Expression Regulation, Leukemic
  • Hematopoietic Stem Cells* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction
  • Wnt Signaling Pathway
  • X-Box Binding Protein 1* / genetics
  • X-Box Binding Protein 1* / metabolism

Substances

  • X-Box Binding Protein 1
  • Endoribonucleases
  • Protein Serine-Threonine Kinases
  • Ern1 protein, mouse
  • Xbp1 protein, mouse
  • XBP1 protein, human
  • ERN1 protein, human