ArticleCancer discovery2016
DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
Article in Cancer discovery, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 97 citations in OpenAlex.
- Co-occurrence of low-grade fibromyxoid sarcoma and familial Tatton-Brown-Rahman syndrome with germline DNMT3A c.1904G > A (p.Arg635Gln): a case report.BMC pediatrics · 2026Article
- P300/CBP inhibition with inobrodib in combination with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML.Science advances · 2026Article
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- Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators.Science advances · 2026Article
- Mutation Patterns Define Clinical Heterogeneity in Acute Myeloid Leukemia.Journal of Cancer · 2026Article
- TLR2 agonism suppresses myeloid leukemogenesis by reprogramming leukemia stem cells.Blood advances · 2025Article
- ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche.Nature communications · 2025Article
- Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway.Nature communications · 2025Article
- Article
- MutantProceedings of the National Academy of Sciences of the United States of America · 2025Article
- STING mediates increased self-renewal and lineage skewing in DNMT3A-mutated hematopoietic stem/progenitor cells.Leukemia · 2025Article
- Significance of targeting DNMT3A mutations in AML.Annals of hematology · 2025Review
- Article
- Star wars against leukemia: attacking the clones.Leukemia · 2024Review
- Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.The Journal of clinical investigation · 2024Article
- Cre recombinase promotes leukemogenesis in the presence of both homozygous and heterozygous FLT3-ITD.Leukemia · 2024Article
- Clonal haematopoiesis across the age spectrum of vasculitis patients with Takayasu's arteritis, ANCA-associated vasculitis and giant cell arteritis.Annals of the rheumatic diseases · 2024Article
- FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.Leukemia · 2024Article
- Article
- The impact of DNMT3A variant allele frequency and two different comutations on patients with de novo cytogenetically normal acute myeloid leukemia.Cancer medicine · 2023Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledCytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. SIGNIFICANCE: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
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