ReviewSeminars in oncology2012
p53-Independent, normal stem cell sparing epigenetic differentiation therapy for myeloid and other malignancies.
Review in Seminars in oncology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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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.
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Who cites it
25 citing papers in PubMed, 53 citations in OpenAlex.
- A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.Seminars in hematology · 2021Trial
- Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.PLoS medicine · 2017Trial
- Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2017Trial
- Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes.The Journal of clinical investigation · 2015Trial
- Trial
- A review on regulation of DNA methylation during post-myocardial infarction.Frontiers in pharmacology · 2024Review
- Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management.American journal of hematology · 2023Review
- DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation.Annals of medicine · 2022Review
- Myelodysplastic syndromes.Nature reviews. Disease primers · 2022Review
- UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress-mediated apoptosis.Molecular oncology · 2020Article
- Targeting sickle cell disease root-cause pathophysiology with small molecules.Haematologica · 2019Review
- Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates.The Journal of clinical investigation · 2018Article
- Fetal Hemoglobin Induction by Epigenetic Drugs.Seminars in hematology · 2018Review
- The Future of Targeting FLT3 Activation in AML.Current hematologic malignancy reports · 2017Review
- The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells.Leukemia · 2016Article
- Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease.Leukemia · 2015Article
- Artesunate-enhanced apoptosis of human high-risk myelodysplastic cells induced by the DNA methyltransferase inhibitor decitabine.Oncology letters · 2015Article
- Novel drugs for older patients with acute myeloid leukemia.Leukemia · 2015Review
- Runx1 regulation of Pu.1 corepressor/coactivator exchange identifies specific molecular targets for leukemia differentiation therapy.The Journal of biological chemistry · 2014Article
- Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation.Oncogenesis · 2013Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.
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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.