Englander Institute for Precision Medicine

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

TitleIRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.
Publication TypeJournal Article
Year of Publication2025
AuthorsBarton BM, Son F, Verma A, Bal SKumar, Tang Q, Wang R, Umphred-Wilson K, Khan R, Trichka J, Dong H, Lentucci C, Chen X, Chen Y, Hong Y, Duy C, Elemento O, Melnick AM, Cao J, Chen X, Glimcher LH, Adoro S
JournalNat Immunol
Date Published2025 Jan 09
ISSN1529-2916
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.

DOI10.1038/s41590-024-02063-w
Alternate JournalNat Immunol
PubMed ID39789376
PubMed Central ID6483843
Grant ListRSG-19-025-01-DDC / / American Cancer Society (American Cancer Society, Inc.) /
K22 CA 218467 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
R01 CA198089 / CA / NCI NIH HHS / United States
R37CA228304 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
ZIA BC 01213 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
T32 AI089474 / AI / NIAID NIH HHS / United States
T32 GM008056 / GM / NIGMS NIH HHS / United States
R01HL146642 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
W81XWH1910524 / / U.S. Department of Defense (United States Department of Defense) /
R01 CA198089 / CA / NCI NIH HHS / United States
T32 AI089474 / AI / NIAID NIH HHS / United States
T32 GM008056 / GM / NIGMS NIH HHS / United States

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