ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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14 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis.Journal of healthcare engineering · 2022Pooled it
- Improving severity grading of chemotherapy-induced myelosuppression in AML via data-driven and model-based deep learning.NPJ systems biology and applications · 2026Article
- Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia.Cell reports. Medicine · 2026Article
- Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.Cell stem cell · 2025Article
- Intersecting Anemias: PARP Inhibitor-Induced Toxicity and Autoimmune Hemolysis-A Case Report.EJHaem · 2025Article
- Molecular insights and clinical implications of DNA methylation in sepsis-associated acute kidney injury: a narrative review.BMC nephrology · 2025Review
- Significance of targeting DNMT3A mutations in AML.Annals of hematology · 2025Review
- Crotonylation of MCM6 enhances chemotherapeutics sensitivity of breast cancer via inducing DNA replication stress.Cell proliferation · 2025Article
- Periplocin Targets HDAC10 to Inhibit NF-κB Signaling and Induce Apoptosis in Myeloid Leukemia Cells.Journal of Cancer · 2025Article
- IL-6 Induces CD45 Expression on Myeloid Cells.Sultan Qaboos University medical journal · 2025Article
- Review
- Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations.Experimental hematology · 2022Review
- DNMT3A-Mutant Leukemia Cells Primed to "Fork It Over" under DNA Damage.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Alterations toCancer research · 2021Review
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Authors and funding
27 authors at 4 institutions in 2 countries.
Funding
Abstract
purposeIn acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. EXPERIMENTAL
designLeukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression.
resultsWe found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism.
conclusionsTogether, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.