DNMT3A Mutations in Acute Myeloid Leukemia

By T. Ley, Li Ding, M. Walter, M. McLellan, T. Lamprecht, David E. Larson, Cyriac Kandoth, J. Payton, Jack Baty, J. Welch and 38 more. New England Journal of Medicine, 2010

924 citations recorded by the source corpus.

BACKGROUND The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. METHODS Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. RESULTS A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. CONCLUSIONS DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/3f2cd350826e1f655d4e890d621dda3b5b3f9b23

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Citations in the corpus

The origin and evolution of mutations in Acute Myeloid Leukemia (2012, background): “By comparing these two subtypes of AML, we were able to distinguish the mutations that are likely to be initiating events in the cytogenetically normal cases, versus the cooperating events that are common to both subtypes; this analysis suggests that mutations in NPM1, DNMT3A, and IDH1 may act as ma”
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia (2013, neutral): “AML with minimal maturation: M0 19 (10)”
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, positive): “These include somatic mutations in chromatin-modifying enzymes (Ernst et al., 2010; Nikoloski et al., 2010) and in DNAmethyltransferases (Ley et al., 2010; Yamashita et al., 2010).”
MLL-rearranged Leukemia is Dependent on Aberrant H3K79 Methylation by DOT1L (2011, positive): “…encoding histone methyltransferase EZH2 and DNA methyltransferase DNMT3a are frequently mutated in hematopoietic malignancies (Ernst et al., 2010; Ley et al., 2010; Morin et al., 2010; Nikoloski et al., 2010), and recent trials have demonstrated clinical efficacy of epigenetic-directed therapies…”
Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal (2014, background): “Finally, we showed that the edges of DNA methylation canyons are highly dynamic in a manner concordant with loss of Dnmt3a function (Jeong et al., 2014; Challen et al., 2012), the mutation of which is associated with hematologic malignancies (Ley et al., 2010; Yan et al., 2011).”
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