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DNMT3A mutations in acute myeloid leukemia.

ABSTRACT: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.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.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.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.).

SUBMITTER: Ley TJ

PROVIDER: S-EPMC3201818 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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DNMT3A mutations in acute myeloid leukemia.

Ley Timothy J TJ Ding Li L Walter Matthew J MJ McLellan Michael D MD Lamprecht Tamara T Larson David E DE Kandoth Cyriac C Payton Jacqueline E JE Baty Jack J Welch John J Harris Christopher C CC Lichti Cheryl F CF Townsend R Reid RR Fulton Robert S RS Dooling David J DJ Koboldt Daniel C DC Schmidt Heather H Zhang Qunyuan Q Osborne John R JR Lin Ling L O'Laughlin Michelle M McMichael Joshua F JF Delehaunty Kim D KD McGrath Sean D SD Fulton Lucinda A LA Magrini Vincent J VJ Vickery Tammi L TL Hundal Jasreet J Cook Lisa L LL Conyers Joshua J JJ Swift Gary W GW Reed Jerry P JP Alldredge Patricia A PA Wylie Todd T Walker Jason J Kalicki Joelle J Watson Mark A MA Heath Sharon S Shannon William D WD Varghese Nobish N Nagarajan Rakesh R Westervelt Peter P Tomasson Michael H MH Link Daniel C DC Graubert Timothy A TA DiPersio John F JF Mardis Elaine R ER Wilson Richard K RK

The New England journal of medicine 20101110 25

<h4>Background</h4>The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.<h4>Methods</h4>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.<h4>Results</h4>A total of 62 of 281 patients ...[more]

PMID: 21067377

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Project description:Background:Acute myeloid leukemia (AML) is a type of cancer that consists of a group of hematological malignancies with high heterogeneity. DNA methyltransferase 3A (DNMT3A)-mutated AML patients have a poor prognosis. Some long non-coding RNAs (lncRNAs) have been reported to enhance therapeutic sensitivity, and so could affect the overall survival rate of elderly cytogenetically normal acute myeloid leukemia (CN-AML) patients; however, studies on the lncRNA signature in DNMT3A-mutated AML are rare. Method:The DNMT3A R878H conditional knock-in mouse model was constructed to explore the lncRNAs of DNMT3A mutation by using the Cuffcomparison method. Cis and trans regulation networks were used to predict candidate genes. The expression levels in leukemic cell lines and the prognostic index of these candidate genes were analyzed with the Broad Institute Cancer Cell Line Encyclopedia (CCLE) and OncoLnc databases. The data for each sample were statistically analyzed using GraphPad Prism. Results:In this study, we applied the DNMT3A R878H conditional knock-in mouse model to explore the lncRNA epigenetic landscape of DNMT3A mutation by using the Cuffcomparison method. Twenty-three differentially expressed lncRNAs were identified in Dnmt3aR878H/WTMx1-Cre+ mice. We next predicted the downstream targetable genes regulated by these lncRNAs through cis and trans regulation networks and found 124 candidate genes are related to these lncRNAs. In further analysis of 124 genes, we found that increased mRNA expression levels of interleukin 1 receptor type 2 (IL1R2), Krüppel-like factor 13 (KLF13), ATPase H+ transporting V1 subunit A (ATP6V1A), proteasome 26S Subunit, non-ATPase 3 (PSMD3), and pyrroline-5-carboxylate reductase 2 (PYCR2) were associated with poor prognosis in AML. Functional analysis of these genes demonstrated that the pathways involved in autophagy, cell cycle, and hematopoietic stem cell differentiation were more enriched in Dnmt3aR878H/WTMx1-Cre+ mice. Conclusion:Our study was the first to use DNMT3A R878H conditional knock-in mouse model to predict the specific lncRNAs regulated by the DNMT3A mutation in AML. Six candidate genes were found to be associated with DNMT3A mutation with poor prognosis. Our results provided a possible treatment strategy for this disease.

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DNMT3A mutations in acute myeloid leukemia.

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DNMT3A mutations in acute myeloid leukemia.

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