Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia

Abstract

Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.

DNMT3A intragenic hypomethylation is associated with adverse prognosis in acute myeloid leukemia

“…In addition, the mutation domain might not affect the status of the CpG island methylation that we analyzed. Jost et al also found that methylation of DNMT3A DMR2 was highly significantly associated with mutations of IDH1, IDH2, RUNX1 and NPM1 genes [28], however, such correlation could not be observed in our data.…”

“…Jost et al identified that DNMT3A hypermethylation was associated with poor outcome [28], however, our study found the adverse impact of aberrant hypomethylation of DNMT3A on the prognosis of AML patients. Especially in CN-AML, Kaplan-Meier analysis revealed that patients with DNMT3A hypomethylation had sig- nificantly shorter OS than those with DNMT3A hypermethylation.…”

“…The expression levels of four isoforms were correlated to each other. In Jost's study, hypermethylation and mutation in DNMT3A gene were found to downregulate relative expression of transcript 2 [28]. However, no correlation of DNMT3A hypomethylation with different transcripts expression was observed in this cohort of AML patients.…”

“…A recent study has identified the opposite results that DNMT3A was methylated in AML patients [28]. However, cells from peripheral blood rather than bone marrow in healthy controls were analyzed in their study.…”

“…Furthermore, in patients with AML, mutation in DNMT3A gene has been suggested to be an adverse prognostic factor [11,27]. Currently, DNMT3A intragenic differentially methylated region 2 (DMR2) hypermethylation was reported to be associated with significantly shorter event-free survival and shorter OS only in the data set of TCGA [28]. The current study was aimed to investigate the methylation status of DNMT3A DMR2 and further analyze its clinical relevance in Chinese AML patients.…”