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Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia.
- Source :
-
Cell reports [Cell Rep] 2018 Oct 30; Vol. 25 (5), pp. 1109-1117.e5. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Activating Transcription Factor 4 metabolism
Animals
Cell Survival
Cytoprotection
Eukaryotic Initiation Factor-2 metabolism
Fetal Blood cytology
Genes, Reporter
Humans
Male
Mice, Inbred NOD
Mice, SCID
Multipotent Stem Cells metabolism
Phosphorylation
Up-Regulation
Valine deficiency
Hematopoiesis
Hematopoietic Stem Cells metabolism
Leukemia metabolism
Stress, Physiological
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 25
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 30380403
- Full Text :
- https://doi.org/10.1016/j.celrep.2018.10.021