Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia

Peter van Galen; Nathan Mbong; Antonia Kreso; Erwin M Schoof; Elvin Wagenblast; Stanley W K Ng; Gabriela Krivdova; Liqing Jin; Hiromitsu Nakauchi; John E Dick

doi:10.1016/j.celrep.2018.10.021

Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia

Cell Rep. 2018 Oct 30;25(5):1109-1117.e5. doi: 10.1016/j.celrep.2018.10.021.

Authors

Affiliations

¹ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
³ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ The Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 1A1, Canada.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁷ Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: john.dick@uhnresearch.ca.

PMID: 30380403
DOI: 10.1016/j.celrep.2018.10.021

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.

Keywords: amino acid deprivation; human hematopoietic stem cells; integrated stress response; leukemia stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4 / metabolism
Animals
Cell Survival
Cytoprotection
Eukaryotic Initiation Factor-2 / metabolism
Fetal Blood / cytology
Genes, Reporter
Hematopoiesis*
Hematopoietic Stem Cells / metabolism*
Humans
Leukemia / metabolism*
Male
Mice, Inbred NOD
Mice, SCID
Multipotent Stem Cells / metabolism
Phosphorylation
Stress, Physiological*
Up-Regulation
Valine / deficiency

Substances

Eukaryotic Initiation Factor-2
Activating Transcription Factor 4
Valine