PURPOSE: Aberrant DNA methylation of promoter-associated CpG islands is an epigenetic DNA modification observed in acute leukemias that in certain cases has been associated with a poor prognosis and increased relapse rates. To study the role of DNA methylation in relapse mechanisms in acute lymphocytic leukemia (ALL), we have compared the methylation status of five genes at the time of initial presentation and at first relapse in 25 adult patients with ALL. EXPERIMENTAL DESIGN: Genes studied included the estrogen receptor (ER), multidrug resistance gene 1 (MDR1), p73, p15, and p16. DNA was extracted from paraffin-embedded bone marrow biopsies. DNA methylation was analyzed using PCR of bisulfite-modified DNA. RESULTS: Results indicate that methylation at the time of relapse was stable in 92% of patients for p73, 88% for ER, 80% for p16, 72% for MDR1, and 60% for p15. Only one case had p16 methylation at initial presentation, whereas 6 patients (P = 0.0001) had methylation at relapse. Three cases had concomitant methylation of p15 and p16 at relapse. The degree of MDR1 methylation inversely correlated with the presence of MDR1 expression as detected by immunohistochemistry. Eighteen patients (72%) had acquired no or one methylation change, whereas the rest (28%) had methylation changes in two or three genes. No clinical-biological correlations were found between methylation of any particular gene or pattern. CONCLUSIONS: In summary, DNA methylation patterns are stable in a majority of patients with relapsed ALL, but a subset of patients acquire new methylation changes, in particular affecting cell cycle regulatory genes.
PURPOSE: Aberrant DNA methylation of promoter-associated CpG islands is an epigenetic DNA modification observed in acute leukemias that in certain cases has been associated with a poor prognosis and increased relapse rates. To study the role of DNA methylation in relapse mechanisms in acute lymphocytic leukemia (ALL), we have compared the methylation status of five genes at the time of initial presentation and at first relapse in 25 adult patients with ALL. EXPERIMENTAL DESIGN: Genes studied included the estrogen receptor (ER), multidrug resistance gene 1 (MDR1), p73, p15, and p16. DNA was extracted from paraffin-embedded bone marrow biopsies. DNA methylation was analyzed using PCR of bisulfite-modified DNA. RESULTS: Results indicate that methylation at the time of relapse was stable in 92% of patients for p73, 88% for ER, 80% for p16, 72% for MDR1, and 60% for p15. Only one case had p16 methylation at initial presentation, whereas 6 patients (P = 0.0001) had methylation at relapse. Three cases had concomitant methylation of p15 and p16 at relapse. The degree of MDR1 methylation inversely correlated with the presence of MDR1 expression as detected by immunohistochemistry. Eighteen patients (72%) had acquired no or one methylation change, whereas the rest (28%) had methylation changes in two or three genes. No clinical-biological correlations were found between methylation of any particular gene or pattern. CONCLUSIONS: In summary, DNA methylation patterns are stable in a majority of patients with relapsed ALL, but a subset of patients acquire new methylation changes, in particular affecting cell cycle regulatory genes.
Authors: Peter E Zage; Riitta Nolo; Wendy Fang; John Stewart; Guillermo Garcia-Manero; Patrick A Zweidler-McKay Journal: Pediatr Blood Cancer Date: 2011-07-08 Impact factor: 3.167
Authors: Anna Scuto; Mark Kirschbaum; Claudia Kowolik; Leo Kretzner; Agnes Juhasz; Peter Atadja; Vinod Pullarkat; Ravi Bhatia; Stephen Forman; Yun Yen; Richard Jove Journal: Blood Date: 2008-03-18 Impact factor: 22.113
Authors: Hui Yang; Tapan Kadia; Lianchun Xiao; Carlos E Bueso-Ramos; Koyu Hoshino; Deborah Ann Thomas; Susan O'Brien; Elias Jabbour; Sherry Pierce; Gary L Rosner; Hagop M Kantarjian; Guillermo Garcia-Manero Journal: Blood Date: 2008-12-23 Impact factor: 22.113