Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia

Abstract

Epigenetic de novo methylation of CpG islands is an important event in malignant transformation. Two genes are frequently methylated: cyclin-dependent kinase inhibitor 2B (CDKN2B) and cyclin-dependent kinase inhibitor 2A (CDKN2A). In our study methylation of these genes was studied in 63 patients with myelodysplastic syndromes (MDS), 2 with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 13 with acute myeloid leukemia (AML). Five patients were monitored during 5-azacytidine treatment. Twenty-six healthy donors were tested in a control group. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method with all associated techniques was used for detection. Aberrant methylation was present in the CDKN2A gene in 38% and in the CDKN2B gene in 77% of the patients in MDS group. The level of methylation was higher in the group of AML patients - 77% in CDKN2A gene and 100% in CDKN2B gene. In MDS patients, an aberrant methylation was associated with a tendency to disease progression towards more advanced forms according to the World Health Organization (WHO) classification and the International Prognostic Scoring System (IPSS). Significant differences in methylation level were observed between early and advanced forms of MDS in CDKN2B gene (P value < 0.05) but not for CDKN2A gene. The trend of methylation in patients treated with azacitidine was analyzed in CDKN2B gene and correlated with the course of the disease. Increased methylation was connected with disease progression. We concluded that the methylation level of CDKN2B gene might be used as a marker of leukemic transformation in MDS. Our study indicates the role of hypermethylation as an important event in the progression of MDS to AML.

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).…”

Genetic and epigenetic alterations of bone marrow stromal cells in myelodysplastic syndrome and acute myeloid leukemia patients

“…In addition, many hematologic neoplasias also acquire epigenetic changes, which may have a profound effect at the level of gene expression (Bonifer and Bowen, 2010;Jelinek et al, 2011). For example, the inactivation of tumor suppressor genes by promoter hypermethylation contributes to the initiation and progression of MDS and AML (Bies et al, 2010;Cechova et al, 2012).…”

The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

“…Previous study has indicated aberrant DNA methylation associated with leukemogenesis [10]. As a typical epigenetic modifications, aberrant DNA methylation was observed in lymphoid/hematopoietic malignancies, including AML [4], [11], CML [12], [13], ALL [1], [14], and CLL [15], [16].…”