Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia

Abstract

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene- and microRNA-expression and DNA methylation profiles in 210 older (≥60 years) adults with primary, cytogenetically normal AML (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene- and microRNA-expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene-expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only 4 differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene-expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

Expression and prognostic impact of lncRNAs in acute myeloid leukemia

“…Whereas recent studies have reported that clinical outcome of older patients with CN-AML is influenced by several recurrent mutations, patients with apparently identical cytogenetic and molecular "makeup" do not have uniform outcomes (11)(12)(13)(14)(15)(16)(17)(18)(19). This may result from additional undiscovered genetic alterations, which may identify smaller, clinically meaningful patient groups for which it is possible to identify specific therapeutic targets.…”

“…Our group reported that nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) mutations are associated with a more favorable outcome in older patients with CN-AML (11), whereas fms-related tyrosine kinase 3 (FLT3) internal tandem duplications (FLT3-ITDs) and mutations in the additional sex combs like transcriptional regulator 1 (ASXL1), runt-related transcription factor 1 (RUNX1) and DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), which affect arginine codon 882 (R882-DNMT3A), are independently associated with worse disease-free survival (DFS) and OS (12)(13)(14)(15). We further showed that high expression levels of the brain and acute leukemia, cytoplasmic (BAALC), v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), meningioma (disrupted in balanced translocation) 1 (MN1), and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) genes are associated with unfavorable outcome in older patients with CN-AML (16)(17)(18).…”

“…Cytogenetic analyses were performed in CALGB/Alliance approved institutional laboratories and confirmed by central karyotype review (49), and the diagnosis of normal karyotype was based on ≥20 metaphase cells analyzed in BM specimens subjected to short-term (24 h or 48 h) unstimulated cultures. Molecular studies shown in Tables S1 and S8 were performed as described in SI Methods and Data and elsewhere (11)(12)(13)(14)(15)(16)(17)(18). The patients in the training and validation sets were treated with intensive cytarabine/ daunorubicin-based therapy on one of the CALGB frontline treatment protocols as described in SI Methods and Data.…”

“…Recent work has identified novel genetic alterations, including gene mutations and changes in gene expression in CN-AML that have improved the classification and risk stratification of this large subgroup of patients (9,10). Whereas most of these studies were performed in younger patients with CN-AML, some studies have investigated the prognostic significance of genetic alterations in older patients (11)(12)(13)(14)(15)(16)(17)(18)(19). Our group reported that nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) mutations are associated with a more favorable outcome in older patients with CN-AML (11), whereas fms-related tyrosine kinase 3 (FLT3) internal tandem duplications (FLT3-ITDs) and mutations in the additional sex combs like transcriptional regulator 1 (ASXL1), runt-related transcription factor 1 (RUNX1) and DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), which affect arginine codon 882 (R882-DNMT3A), are independently associated with worse disease-free survival (DFS) and OS (12)(13)(14)(15).…”

miR-133b, a microRNA targeting S1PR1, suppresses nasopharyngeal carcinoma cell proliferation

“…Niederwieser et al (17) reported that high expression levels of DNA (cytosine-5-)-methyltransferase 3β were associated with differentially expressed miR-133b in older adults with primary, cytogenetically normal acute myeloid leukemia. Therefore, the present study hypothesized that epigenetic factors may contribute to the downregulation of miR-133b, although this requires further investigation in future studies.…”