Integrated stress response activity marks stem cells in normal hematopoiesis and leukemia
Open accessAbstract
Lifelong maintenance of the blood system requires equilibrium between clearance of damaged hematopoietic stem cells (HSCs) and long-term survival of the HSC pool. Severe perturbations of cellular homeostasis result in rapid HSC loss to maintain clonal purity. However, normal homeostatic processes can also generate lower-level stress; how HSCs survive these conditions remains unknown. Here we show that the integrated stress response (ISR) is uniquely active in HSCs and facilitates their persistence. Activating transcription factor 4 (ATF4) mediates the ISR and is highly expressed in HSCs due to scarcity of the eIF2 translation initiation complex. Amino acid deprivation results in eIF2α phosphorylation-dependent upregulation of ATF4, promoting HSC survival. Primitive acute myeloid leukemia (AML) cells also display eIF2 scarcity and ISR activity marks leukemia stem cells (LSCs) in primary AML samples. These findings identify a link between the ISR and stem cell survival in the normal and leukemic contexts.
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In both hematopoietic stem cells and LSCs, specific translation dynamics lead to activation of the ISR.
“In both hematopoietic stem cell and LSC, specific translation dynamics lead to activation of the ISR.55”
From CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells (2021) · cites this paper as [55]
LSCs possess a distinct pro-survival integrated stress response (ISR) that mirrors that of normal hematopoietic stem cells.
“Our recent studies have shown that LSCs possess a distinct pro-survival ISR 50 that mirrors that of normal hematopoietic stem cells.55,56”
From CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells (2021) · cites this paper as [55]
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- Authors
- van Galen, P., Mbong, N., Kreso, A., Schoof, E. M., Wagenblast, E., Ng, S. W. K., Krivdova, G., Jin, L., Nakauchi, H., & Dick, J. E.
- Affiliations
- University Health Network (CA)
- Massachusetts General Hospital (US)
- University of Copenhagen (DK)
- Stanford Medicine (US)
- Corresponding author
- Dick, John E.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 25
- Issue
- 5
- Pages
- 1109-1117.e5
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2899451374
- Cited by
- 131
- References
- 42
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 18 · 2023: 15 · 2022: 23 · 2021: 16 · 2020: 18 · 2019: 7 · 2012: 1
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Funders
- Leukemia and Lymphoma Society (5458-17)
- European Molecular Biology Organization (ALTF 1595-2014)
- European Commission (LTFCOFUND2013, GA-2013-609409)
- Marie Curie Actions
- Human Frontier Science Program
- Canadian Institutes for Health Research
- Canadian Cancer Society Research Institute
- Terry Fox Foundation
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- Canada Research Chair
- Princess Margaret Hospital Foundation
- Ontario Ministry of Health and Long Term Care
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- integrated stress response, hematopoietic stem cells, leukemia stem cells, acute myeloid leukemia, ATF4, eIF2α phosphorylation, amino acid starvation, stem cell homeostasis
- MeSH terms
- Animals, Cell Survival, Fetal Blood, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukemia, Male, Phosphorylation, Stress, Physiological, Valine, Eukaryotic Initiation Factor-2, Up-Regulation, Mice, SCID, Mice, Inbred NOD, Genes, Reporter, Cytoprotection, Multipotent Stem Cells, Activating Transcription Factor 4
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