Promoter hypermethylation of p15^INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early‐stage patients

Abstract

The propensity of myelodysplastic syndrome (MDS) to transform into acute myeloid leukemia (AML) suggests the existence of common pathogenic components for these malignancies. Here, four genes implicated in the development of AML were examined for promoter CpG island hypermethylation in cells from 37 patients with different stages of MDS. Aberrant methylation was detected by polymerase chain reaction amplification of bisulfite-treated DNA followed by denaturing gradient gel electrophoresis. The highest rate of methylation was found for p15INK4B (51%), followed by HIC1 (32%), CDH1 (27%), and ER (19%). Concurrent hypermethylation of > or = 3 genes was more frequent in advanced compared with early-stage MDS (P < or = 0.05), and hypermethylation of p15INK4B was associated with leukemic transformation in early MDS (P < or = 0.05). The median overall survival was 17 months for cases showing hypermethylation of > or = 1 genes vs. 67 months for cases without hypermethylation (P = 0.002). Specifically, promoter hypermethylation identified a subgroup of early MDS with a particularly poor prognosis (median overall survival 20 months vs. 102 months; P = 0.004). In multivariate analysis including stage and thrombocyte count, hypermethylation of > or = 1 genes was an independent negative prognostic factor (P < 0.05). These data suggest that hypermethylation of p15INK4B, HIC1, CDH1, and ER contribute to the development and outcome of MDS.

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

“…The majority of bibliographic data though support the idea that p21 may act as an apoptosis inhibitor, in contradiction to our results [44]. There are yet a number of reports that suggest a pro-apoptotic function of p21 under certain conditions in specific systems and are in agreement with our findings [47][48][49][50][51][52][53][54][55][56]. Further investigation of the role of p21 in apoptosis is required.…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…(Figure 4). The E-cadherin (CDH1) gene is hypermethylated and transcriptionally repressed in gastric and breast cancers, myeloid malignancies, and other tumors (Cowin et al, 2005;Aggerholm et al, 2006;Chan, 2006). We observed hypermethylation of the CDH1 CpG island (Figure 4a), corresponding to a 2.19-fold decrease in gene expression (Figure 3).…”

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

“…Mainly by deregulation of the cell cycle and the TGF-β pathway (Matsuno et al, 2005). Hypermethylation of p15 gene was reported in myelodysplastic syndrome (MDS), and may play role in progression of MDS to AML (Aggerholm et al, 2006;Hofmann et al, 2006;Cechova et al, 2012). Silencing of p16 gene by hypermethylation was shown to be mediated by a similar mechanism to p14 and TMS1 gene silencing (Esteller, 2002).…”