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

TY - JOUR

T1 - Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia

AU - van Galen, Peter

AU - Mbong, Nathan

AU - Kreso, Antonia

AU - Schoof, Erwin M.

AU - Wagenblast, Elvin

AU - Ng, Stanley W.K.

AU - Krivdova, Gabriela

AU - Jin, Liqing

AU - Nakauchi, Hiromitsu

AU - Dick, John E.

PY - 2018

Y1 - 2018

N2 - 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. Hematopoietic stem cells balance apoptosis with survival to maintain lifelong integrity of the blood system. Van Galen et al. show that specific translation dynamics prime normal and leukemia stem cells to activate the integrated stress response, which can enhance survival in the presence of stressors such as amino acid deprivation.

AB - 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. Hematopoietic stem cells balance apoptosis with survival to maintain lifelong integrity of the blood system. Van Galen et al. show that specific translation dynamics prime normal and leukemia stem cells to activate the integrated stress response, which can enhance survival in the presence of stressors such as amino acid deprivation.

KW - amino acid deprivation

KW - human hematopoietic stem cells

KW - integrated stress response

KW - leukemia stem cells

U2 - 10.1016/j.celrep.2018.10.021

DO - 10.1016/j.celrep.2018.10.021

M3 - Journal article

C2 - 30380403

AN - SCOPUS:85055257212

SN - 2211-1247

VL - 25

SP - 1109-1117.e1-e5

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -