ArticleDevelopmental cell2024
Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.
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Article in Developmental cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed.
- Article
- Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.bioRxiv : the preprint server for biology · 2026Article
- Size-Dependent Metabolic Reprogramming in A549 Cells Induced by Mesoporous Silica Nanoparticles: Insights from Subcellular Targeting.Metabolites · 2026Article
- ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.Nature communications · 2026Article
- Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.Nature metabolism · 2026Article
- OGDHL Promotes Prostate Cancer Progression and Regulates Neuroendocrine Marker Expression and Nucleotide Abundance.Molecular cancer research : MCR · 2026Article
- Sodium butyrate suppresses endometrial cancer cell growth by inhibiting thymidylate synthase and reprogramming pyrimidine metabolism.Genes & nutrition · 2026Article
- DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.Cell death & disease · 2026Article
- Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.Cell death discovery · 2026Article
- The oncogenic control of nucleotide synthesis.Oncogenesis · 2026Review
- Automated mapping of DNA replication fork progression in human cells with ForkML.Nature communications · 2026Article
- Article
- Loss of UXS1 Selectively Depletes Pyrimidines and Induces Replication Stress in KEAP1-Mutant Lung Cancer.Cancer research · 2025Article
- Hematopoietic Stem Cell Hierarchies as Novel Biomarkers of Drug Response in Myelodysplastic Syndromes and Acute Myeloid Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Review
- OGDHL regulates tumor growth, neuroendocrine marker expression, and nucleotide abundance in prostate cancer.bioRxiv : the preprint server for biology · 2025Article
- Biological and clinical implications of a model of surveillance immunity.The Journal of clinical investigation · 2025Review
- Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.bioRxiv : the preprint server for biology · 2025Article
- Histone chaperones coupled to DNA replication and transcription control divergent chromatin elements to maintain cell fate.Genes & development · 2025Article
- Article
- Article
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Authors and funding
26 authors.
Brian T DoKoch 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.
Peggy P HsuKoch 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.
Sidney Y VermeulenKoch 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.
Zhishan WangKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Taghreed HirzCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Keene L AbbottKoch 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.
Najihah AzizCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Joseph M ReplogleWhitehead Institute for Biomedical Research, Cambridge, MA 02139, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Stefan BjelosevicBroad 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.
Jonathan PaolinoDepartment 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.
Samantha A NelsonKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Samuel BlockKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Alicia M DarnellKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Raphael FerreiraKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
Hanyu ZhangCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Jelena MilosevicCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Daniel R SchmidtKoch 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.
Christopher ChidleyLaboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Isaac S HarrisWilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
Jonathan S WeissmanKoch 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.
Yana PikmanDepartment 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.
Kimberly StegmaierBroad 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.
Sihem CheloufiDepartment 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.
Xiaofeng A SuKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
David B SykesCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02113, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
Matthew G Vander HeidenKoch 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.
Funding
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Paula T Hammond · 1985 to 2026
$93.9MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MPRE-DOCTORAL TRAINING IN THE BIOLOGICAL SCIENCEST32GM007287 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BELL, STEPHEN P., KEATING, AMY E · 1985 to 2019
$40.8MPATHOPHYSIOLOGY OF HUMAN BLOOD CELLST32HL007574 · NHLBI · CHILDREN'S HOSPITAL BOSTON · PI Daniel Evan Bauer · 1985 to 2026
$18.4MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MSystems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule DrugsU54CA225088 · NCI · HARVARD MEDICAL SCHOOL · PI SORGER, PETER KARL · 2018 to 2022
$10.8MTraining Program in Cancer Biology and TherapeuticsT32CA071345 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Daniel A. Haber, Lecia V. Sequist · 1997 to 2026
$10.6MStem Cell and Transplantation BiologyU54DK106829 · NIDDK · FRED HUTCHINSON CANCER RESEARCH CENTER · PI DEREK L STIREWALT · 2015 to 2026
$9.1MUnderstanding the role of metabolism in cancerR35CA242379 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI VANDER HEIDEN, MATTHEW G. · 2019 to 2025
$5.8MImproving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolismR01CA259253 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K., VANDER HEIDEN, MATTHEW G. · 2021 to 2025
$2.3MImpact of extracellular glutathione catabolism on triple-negative breast cancerR01CA269813 · NCI · UNIVERSITY OF ROCHESTER · PI Jeevisha Bajaj · 2022 to 2026
$2.2MInvestigating the Regulatory Roles of Histone Chaperones in Cellular PlasticityR35GM151004 · NIGMS · UNIVERSITY OF CALIFORNIA RIVERSIDE · PI Sihem Cheloufi · 2023 to 2026
$1.6MNCI NIH HHS F31 CA271787NCI NIH HHS P30 CA014051NCI NIH HHS R01 CA259253NCI NIH HHS R01 CA269813NCI NIH HHS R35 CA242379NCI NIH HHS T32 CA071345NCI NIH HHS U54 CA225088NHLBI NIH HHS F30 HL156404NHLBI NIH HHS T32 HL007574NIDDK NIH HHS U54 DK106829NIGMS NIH HHS R35 GM151004NIGMS NIH HHS T32 GM007287NIGMS NIH HHS T32 GM007753NIGMS NIH HHS T32 GM144273NINDS NIH HHS F31 NS115380
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.
Indexed as
Cell DifferentiationDNA ReplicationAnimalsCell LineageHumansLeukemia, Myeloid, AcuteMiceNucleotidesSignal TransductionS PhaseNucleotidescancercell fatecell statedependenciesdifferentiationepigeneticshematopoiesismetabolismnucleotidesreplicationreplication stress
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