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Updated: Feb 3, 2026

Ex vivo Mimicry of Normal and Abnormal Human Hematopoiesis
Published on: April 10, 2012
Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia
Peter van Galen1, Nathan Mbong2, Antonia Kreso3
1Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
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.
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