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

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

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

Author(s) -

Peter van Galen,

Nathan Mbong,

Antonia Kreso,

Erwin M. Schoof,

Elvin Wagenblast,

Stanley Ng,

Gabriela Krivdova,

Liqing Jin,

Hiromitsu Nakauchi,

John E. Dick

Publication year - 2018

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2018.10.021

Subject(s) - haematopoiesis , integrated stress response , stem cell , biology , myeloid leukemia , leukemia , microbiology and biotechnology , downregulation and upregulation , hematopoietic stem cell , homeostasis , myeloid , transcription factor , immunology , cancer research , translation (biology) , genetics , messenger rna , gene

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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