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

IF 27.7 1区医学 Q1 IMMUNOLOGY

Nature Immunology Pub Date : 2025-01-09 DOI:10.1038/s41590-024-02063-w

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

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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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来源期刊

Nature Immunology 医学-免疫学

CiteScore

40.00

自引率

2.30%

发文量

248

审稿时长

4-8 weeks

期刊介绍： Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.