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. GlimcherStanley Adoro

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

3 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.",

year = "2025",

month = feb,

day = "1",

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.

KW - X-Box Binding Protein 1/metabolism

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

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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

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Keywords

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