Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia

Abstract

Hypermethylation of CpG islands near gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in carcinogenesis. Such epigenetic phenomena can act alongside DNA mutations and deletions to disrupt tumor-suppressor gene function. The methylation status of the promoter-associated CpG islands from 11 well-characterized cancer-related genes was analyzed by methylation-specific polymerase chain reaction in 60 adult patients with acute myelogenous leukemia (AML) at diagnosis. The frequency of aberrant methylation among the patient samples was 45.0% (27/60) for suppressor of cytokine signaling-1, 31.7% (19/60) for p15, 20.0% (12/60) for retinoic acid receptor beta2, 13.3% (8/60) for p73 and E-cadherin, 5.0% (3/60) for O(6)-methylguanine DNA methyltransferase, 3.3% (2/60) for death-associated protein kinase 1 and hMLH1, 1.7% (1/60) for p16, and 0% (0/60) for the tissue inhibitor of matrix metalloproteinases-3 and Ras association domain family 1A. Aberrant DNA methylation was found in AML of all French-American-British subtypes and throughout all cytogenetic risk groups. There appeared to be a trend towards a higher methylation frequency in AML patients with an unfavorable karyotype, but this difference was not statistically significant. Our data indicate that hypermethylation of multiple genes involving fundamental cellular pathways is a common event in AML, which varies greatly in frequency among the genes examined. The accumulation of epigenetic events affecting genes which are involved in regulating cell cycle inhibition, cell adhesion, growth factor signaling, and apoptosis may contribute to the malignant AML phenotype. The growing knowledge of the role of epigenetics in the aberrant silencing of cancer-related genes provides a rationale and molecular basis for targeted therapeutic approaches with demethylating agents in AML.

DNA profiling analysis of 100 consecutive de novo acute myeloid leukemia cases reveals patterns of genomic instability that affect all cytogenetic risk groups

“…29,30 Many of these differences may have originated through mutational or epigenetic alterations that contributed to the variability of the disease. 31,32 Other molecular cytogenetic techniques have also unveiled new chromosomal rearrangements which were not visible by karyotyping. [16][17][18][19]33,34 We have used a genomic array with more than 40 000 probes that offers a median resolution of 75 kb and whose composition is biased towards known genes.…”

Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia

“…6 Although methylation of other genes has been shown to associate with prognosis, the results are somewhat contradictory. [7][8][9] In high-risk myelodysplastic syndrome (MDS) and in AML after MDS, methylation of CDKN2b (p15), E-cadherin (CDH) and hypermethylated in cancer 1 (HIC1) have recently been shown to be associated with failure to achieve complete remission (CR) after induction chemotherapy. 10 We analyzed gene-specific promoter methylation of p15, CDH and HIC1 as well as global DNA methylation using the luminometric methylation assay (LUMA) technique in a well-characterized cohort of 107 AML patients.…”

An epigenomic mechanism in retinoblastoma: the end of the story?

“…[2] are indeed encouraging, SYK is unlikely to be the only answer. Epigenetic alterations are widespread in many if not most malignancies, pediatric and adult alike, as shown by recent data on adult acute myeloid leukemia and colorectal cancer [4,5]. In childhood cancer, aberrant methylation of chromosome 11p in Wilms' tumor, embryonal rhabdomyosarcoma, hepatoblastoma and Beckwith-Wiedemann syndrome (BWS) is well documented, often a consequence of uniparental disomy.…”