Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia

Abstract

Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…We and others 24,25,29 --31,44 found that DNMT3A mutations were strongly associated with FAB M4/M5 subtypes, and often co-occurred with NPM1 or IDH1 mutations in AML patients, suggesting that the oncogenic actions of these mutations are not redundant. DNMT3A mutations were reported to be associated with older age, 24,25,30,31 but this feature was not observed in our cohort of adult CN-AML. Nevertheless, a link between age and the incidence of DNMT3A mutations is likely as these mutations seem to be extremely rare (o1%) in pediatric AML.…”

“…45 --47 Among the 11 different DNMT3A mutations identified in our cohort, those affecting R882 residue were the most common, in agreement with previous reports. 24,25,29 Interestingly, the somatic R882 mutations in DNMT3A found in AML are analogous to the inherited R823G mutation in DNMT3B, which was discovered in a human syndrome characterized by immunodeficiency, centrosome instability and facial abnormalities (ICF) in association with defects in genomic methylation. 48,49 In AML, the exact pathogenic mechanism by which DNMT3A mutations act is still enigmatic.…”

“…However, the leukemogenic potential of DNMT3A mutations remains to be proven at an organism level. 25 Most DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. 25,26 Using methyl-DNA immunoprecipitation chip analysis in AML samples with DNMT3A R882 mutations, Ley et al 24 identified 182 genomic regions with decreases in DNA methylation, while Yan et al 25 found almost 4000.…”

“…25 Most DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. 25,26 Using methyl-DNA immunoprecipitation chip analysis in AML samples with DNMT3A R882 mutations, Ley et al 24 identified 182 genomic regions with decreases in DNA methylation, while Yan et al 25 found almost 4000. Anyway, DNMT3A mutations did not yield a specific pattern of altered DNA methylation, unlike other recurrent genetic abnormalities in AML, such as PML-RARA, CBFB-MYH11 or double CEBPA mutations.…”

“…50 Likewise, the influence of DNMT3A mutational status on gene expression profiles is yet unclear, and DNMT3A mutant AML was not found to have a common gene expression signature. 24,25 Further experiments are needed to identify genes whose expression is modulated by DNMT3A mutations and determine the biological effects of these mutations. We showed that DNMT3A mutations confer a poor prognosis in CN-AML, in line with previous studies in AML.…”