ArticleLeukemia2021
Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.
Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07283094 (FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia), which is not on this map. Cited by 72 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia
Who cites it
72 citing papers in PubMed, 99 citations in OpenAlex.
- Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.Seminars in hematology · 2021Trial
- Functional characterization of the 9q34.13 locus identifies RAPGEF1 as a candidate gene modulating risk for melanoma and nevi via RAS activation.American journal of human genetics · 2026Article
- Review
- Targeting CDK7 to overcome hypomethylating agent resistance in acute myeloid leukemia.Blood research · 2026Article
- Reduced Maintenance DNA Methylation Thresholds Enable Sensitive Reporter Assays for UHRF1 and DNMT1 Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Initial leukemic epigenomic state determines hypomethylating agent response.Nature communications · 2026Article
- Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.Oncogenesis · 2026Article
- Uridine cytidine kinases govern molnupiravir bioactivation and anti-SARS-CoV-2 activity.PLoS pathogens · 2026Article
- Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Epidrugs in cancer: mechanisms, applications, and future direction.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Article
- Gastrointestinal adverse reactions and metabolism-nutrition disorders associated with hypomethylating agents: a pharmacovigilance study with exploratory mechanistic analysis.Frontiers in nutrition · 2026Article
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.Journal for immunotherapy of cancer · 2025Article
- Article
- Article
- Cytidine and dCMP Deaminases-Current Methods of Activity Analysis.International journal of molecular sciences · 2025Review
- Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity.bioRxiv : the preprint server for biology · 2025Article
- Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents.bioRxiv : the preprint server for biology · 2025Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients' bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation. Further investigation revealed the origin of these shifts. Pyrimidine metabolism is a network that senses and regulates deoxynucleotide amounts. Deoxynucleotide amounts were disturbed by single exposures to decitabine or 5-azacytidine, via off-target depletion of thymidylate synthase and ribonucleotide reductase respectively. Compensating pyrimidine metabolism shifts peaked 72-96 h later. Continuous pro-drug exposures stabilized these adaptive metabolic responses to thereby prevent DNMT1-depletion and permit exponential leukemia out-growth as soon as day 40. The consistency of the acute metabolic responses enabled exploitation: simple treatment modifications in xenotransplant models of chemorefractory leukemia extended noncytotoxic DNMT1-depletion and leukemia control by several months. In sum, resistance to decitabine and 5-azacytidine originates from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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 OpenQuestion graph.