IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs PMID: 39789376

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
# Contributed equally.

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.