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

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

National Institutes of Health
Case Western Reserve University
Cornell University
Sichuan Agricultural University
Dana-Farber Cancer Institute
La Trobe University
University of Texas MD Anderson Cancer Center
Zhejiang University
Harvard University

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English
Article number	2290
Pages (from-to)	200-214
Number of pages	15
Journal	Nature Immunology
Volume	26
Issue number	2
DOIs	https://doi.org/10.1038/s41590-024-02063-w
State	Published - Feb 1 2025

Keywords

X-Box Binding Protein 1/metabolism
Animals
Endoribonucleases/metabolism
Hematopoietic Stem Cells/metabolism
Protein Serine-Threonine Kinases/metabolism
Humans
Mice
Leukemia, Myeloid, Acute/genetics
Signal Transduction
Mice, Knockout
Wnt Signaling Pathway
Gene Expression Regulation, Leukemic
Mice, Inbred C57BL

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Barton, B. M., Son, F., Verma, A., Bal, S. K., 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, A. M., Cao, J., Chen, X., ... Adoro, S. (2025). IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs. Nature Immunology, 26(2), 200-214. Article 2290. https://doi.org/10.1038/s41590-024-02063-w

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title = "IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs",

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.",

keywords = "X-Box Binding Protein 1/metabolism, Animals, Endoribonucleases/metabolism, Hematopoietic Stem Cells/metabolism, Protein Serine-Threonine Kinases/metabolism, Humans, Mice, Leukemia, Myeloid, Acute/genetics, Signal Transduction, Mice, Knockout, Wnt Signaling Pathway, Gene Expression Regulation, Leukemic, Mice, Inbred C57BL",

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

note = "{\textcopyright} 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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doi = "10.1038/s41590-024-02063-w",

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Barton, BM, Son, F, Verma, A, Bal, SK, 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 2025, 'IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs', Nature Immunology, vol. 26, no. 2, 2290, pp. 200-214. https://doi.org/10.1038/s41590-024-02063-w

TY - JOUR

T1 - IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

AU - Barton, Brendan M.

AU - Son, Francheska

AU - Verma, Akanksha

AU - Bal, Saswat Kumar

AU - Tang, Qianzi

AU - Wang, Rui

AU - Umphred-Wilson, Katharine

AU - Khan, Rehan

AU - Trichka, Josephine

AU - Dong, Han

AU - Lentucci, Claudia

AU - Chen, Xi

AU - Chen, Yinghua

AU - Hong, Yuning

AU - Duy, Cihangir

AU - Elemento, Olivier

AU - Melnick, Ari M.

AU - Cao, Jin

AU - Chen, Xi

AU - Glimcher, Laurie H.

AU - Adoro, Stanley

PY - 2025/2/1

Y1 - 2025/2/1

N2 - 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.

AB - 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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KW - Animals

KW - Endoribonucleases/metabolism

KW - Hematopoietic Stem Cells/metabolism

KW - Protein Serine-Threonine Kinases/metabolism

KW - Humans

KW - Mice

KW - Leukemia, Myeloid, Acute/genetics

KW - Signal Transduction

KW - Mice, Knockout

KW - Wnt Signaling Pathway

KW - Gene Expression Regulation, Leukemic

KW - Mice, Inbred C57BL

UR - https://www.scopus.com/pages/publications/85217731390

U2 - 10.1038/s41590-024-02063-w

DO - 10.1038/s41590-024-02063-w

M3 - Article

C2 - 39789376

SN - 1529-2908

VL - 26

SP - 200

EP - 214

JO - Nature Immunology

JF - Nature Immunology

IS - 2

M1 - 2290

ER -

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

Abstract

Keywords

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