Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

Abstract

Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O 6 MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O 6 MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI ¼ number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children X10 years old and children presenting with high WBC (X50 Â 10 9 /l) both associated with a higher MI (Po0.01 and o0.05, respectively). T-ALLs demonstrated a lower MI (median ¼ 0.17) than precursor B ALLs (median ¼ 0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean ¼ 0.35), while ALLs carrying the t(1;19) had the lowest MI (mean ¼ 0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

The role of p73 in hematological malignancies

“…P73 methylation was also found in childhood ALL. 53 Moreover, P73 is selectively methylated in one-third of patients with Burkitt's lymphoma. 54 Consequently, a loss of p73 mRNA expression, associated with P73 gene hypermethylation, occurred in approximately 28% of B-lineage and 43% of T-lineage cell lines tested.…”

Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes

“…Concurrent methylation of multiple genes occurs in ALL [1][2][3][4]. However, it is still unclear how does this impact upon deregulation of cell proliferation in childhood and adult ALL.…”

“…However, it is still unclear how does this impact upon deregulation of cell proliferation in childhood and adult ALL. Early indications suggest that p14 and p16 are rarely methylated in ALL [2][3][4], although Roman-Gomez et al [1] recently reported a higher frequency. The methylation status of the CIP/ KIP family is not completely known.…”

“…Methylation of p21 appears now to be rare in most cancers [6]. p73 is methylated in about 20% of childhood and adult ALL [1][2][3][4] while data is scarce for p27, p53, and Rb. One-fourth of non-Ph1 ALLs with poor outcome in adults carries methylation in one gene from each family, i.e., p73, p57, and p15 [5].…”

Death associated protein kinase-1 gene methylation pattern in some leukemic patients attending Zagazig University hospitals: is it a clue?

“…14 In South Korean population DAPK1 promoter had 94.3% methylation in ocular adnexal lymphoma. 15 In different haematological malignancies aberrant 28% DAPK1 methylation was reported.…”