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

Brendan M Barton^#^{1

2}, Francheska Son^#², Akanksha Verma^#³, Saswat Kumar Bal², Qianzi Tang⁴, Rui Wang⁴, Katharine Umphred-Wilson^{1

2}, Rehan Khan², Josephine Trichka^{1

2}, Han Dong⁵, Claudia Lentucci⁵, Xi Chen⁶, Yinghua Chen⁷, Yuning Hong⁸, Cihangir Duy⁹, Olivier Elemento³, Ari M Melnick¹⁰, Jin Cao^{11

12}, Xi Chen¹¹, Laurie H Glimcher^{5

13}, Stanley Adoro¹⁴

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

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

Brendan M Barton et al. Nat Immunol. 2025 Feb.

. 2025 Feb;26(2):200-214.

doi: 10.1038/s41590-024-02063-w. Epub 2025 Jan 9.

Authors

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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Conflict of interest statement

Competing interests: L.H.G. is a former Director of Bristol Myers Squibb and the Waters Corporation and currently serves on the Board of Directors of GlaxoSmithKline Pharmaceuticals and Analog Devices. L.H.G. also serves on the scientific advisory boards of Repare Therapeutics, Abpro Therapeutics and Kaleido Therapeutics. A.M.M. receives research funding from Janssen, Daiichi Sankyo and Sanofi; has consulted for Epizyme, Constellation, BMI and Exo-Therapeutics; and is a scientific advisor to KDAC. A.V. is a current employee of Volastra Therapeutics. All other authors declare no competing interests.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials