Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Brian T Do; Peggy P Hsu; Sidney Y Vermeulen; Zhishan Wang; Taghreed Hirz; Keene L Abbott; Najihah Aziz; Joseph M Replogle; Stefan Bjelosevic; Jonathan Paolino; Samantha A Nelson; Samuel Block; Alicia M Darnell; Raphael Ferreira; Hanyu Zhang; Jelena Milosevic; Daniel R Schmidt; Christopher Chidley; Isaac S Harris; Jonathan S Weissman; Yana Pikman; Kimberly Stegmaier; Sihem Cheloufi; Xiaofeng A Su; David B Sykes; Matthew G Vander Heiden

doi:10.1016/j.devcel.2024.05.010

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Dev Cell. 2024 Aug 19;59(16):2203-2221.e15. doi: 10.1016/j.devcel.2024.05.010. Epub 2024 May 31.

Authors

Brian T Do¹, Peggy P Hsu², Sidney Y Vermeulen³, Zhishan Wang⁴, Taghreed Hirz⁵, Keene L Abbott⁶, Najihah Aziz⁵, Joseph M Replogle⁷, Stefan Bjelosevic⁸, Jonathan Paolino⁹, Samantha A Nelson⁴, Samuel Block⁴, Alicia M Darnell⁴, Raphael Ferreira¹⁰, Hanyu Zhang⁵, Jelena Milosevic⁵, Daniel R Schmidt¹¹, Christopher Chidley¹², Isaac S Harris¹³, Jonathan S Weissman¹⁴, Yana Pikman⁹, Kimberly Stegmaier⁸, Sihem Cheloufi¹⁵, Xiaofeng A Su⁴, David B Sykes⁵, Matthew G Vander Heiden¹⁶

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02113, USA; Rogel Cancer Center and Division of Hematology and Oncology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: hsupe@med.umich.edu.
³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
⁶ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹² Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
¹³ Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
¹⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
¹⁵ Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA; Stem Cell Center, University of California, Riverside, Riverside, CA 92521, USA; Center for RNA Biology and Medicine, Riverside, CA 92521, USA.
¹⁶ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mvh@mit.edu.

PMID: 38823395
PMCID: PMC11444020 (available on 2025-08-19)
DOI: 10.1016/j.devcel.2024.05.010

Abstract

Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.

Keywords: cancer; cell fate; cell state; dependencies; differentiation; epigenetics; hematopoiesis; metabolism; nucleotides; replication; replication stress.

MeSH terms

Animals
Cell Differentiation* / genetics
Cell Lineage / genetics
DNA Replication* / genetics
Humans
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mice
Nucleotides / genetics
Nucleotides / metabolism
S Phase / genetics
Signal Transduction

Substances

Nucleotides

Abstract

MeSH terms

Substances

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