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

Brendan M Barton; Francheska Son; Akanksha Verma; Saswat Kumar Bal; Qianzi Tang; Rui Wang; Katharine Umphred-Wilson; Rehan Khan; Josephine Trichka; Han Dong; Claudia Lentucci; Xi Chen; Yinghua Chen; Yuning Hong; Cihangir Duy; Olivier Elemento; Ari M Melnick; Jin Cao; Xi Chen; Laurie H Glimcher; Stanley Adoro

doi:10.1038/s41590-024-02063-w

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.

Authors

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

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

Abstract

MeSH terms

Substances

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