2. Academic Validation
  3. IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

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.
Brendan M Barton # 1 2,  Francheska Son # 2,  Akanksha Verma # 3,  Saswat Kumar Bal 2,  Qianzi Tang 4,  Rui Wang 4,  Katharine Umphred-Wilson 1 2,  Rehan Khan 2,  Josephine Trichka 1 2,  Han Dong 5,  Claudia Lentucci 5,  Xi Chen 6,  Yinghua Chen 7,  Yuning Hong 8,  Cihangir Duy 9,  Olivier Elemento 3,  Ari M Melnick 10,  Jin Cao 11 12,  Xi Chen 11,  Laurie H Glimcher 5 13,  Stanley Adoro 14
Affiliations

Affiliations

  • 1 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 3 Institute of Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 4 College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
  • 5 Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 6 Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
  • 7 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 8 Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
  • 9 Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 10 Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
  • 11 Department of Experimental Therapeutics, James P. Allison Institute, MD Anderson Cancer Center, Houston, TX, USA.
  • 12 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Key Laboratory of Molecular Cancer Biology, Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 13 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 14 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. stanley.adoro@nih.gov.
  • # Contributed equally.
PMID: 39789376 DOI: 10.1038/s41590-024-02063-w
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-104040
    99.95%, IRE1α RNase Inhibitor