DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia.
OBJECTIVE
Aberrant methylation of promoter-associated CpG islands is an epigenetic oncogenic mechanism. The objective of this study was to define the methylation characteristics of patients with acute lymphocytic leukemia (ALL).


METHODS
Using bisulfite-PCR followed by restriction enzyme digestion (COBRA), we have analyzed the methylation status of 10 promoter-associated CpG islands in 80 untreated adult patients with ALL.


RESULTS
Mean methylation density of MDR1, THBS2, MYF3, ER, p15, THBS1, CD10, C-ABL, and p16 was 24.5%, 20.8%, 17.6%, 16.1%, 11.3%, 8.9%, 4.5%, 3.7%, and 1.3% respectively. p73 was methylated in 17 of 80 cases (21.2%). A total of 86.2% of the cases had methylation of at least one gene, and 42.5% of the cases had methylation of three or more genes. MDR1 methylation was inversely correlated with age (P = 0.01). CD10 methylation inversely correlated with CD10 expression (P = 0.0001). Methylation of MDR1 and THBS1 was inversely associated with the presence of the Philadelphia chromosome, whereas C-ABL methylation correlated with the presence of the p210 variant of the Philadelphia chromosome. In univariate analysis, methylation of THBS1 was associated with a favorable outcome (P = 0.02), whereas methylation of p73, p15, and C-ABL was associated with a trend toward worse prognosis.


CONCLUSIONS
Aberrant DNA methylation of promoter-associated CpG islands is very common in adult ALL and potentially defines subgroups with distinct clinical and biological characteristics.
Departments of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ggarciam@mdanderson.org
Guillermo
G
Garcia-Manero
Jerry
J
Daniel
Terry L
TL
Smith
Steven M
SM
Kornblau
Ming-Sheng
MS
Lee
Hagop M
HM
Kantarjian
Jean-Pierre J
JP
Issa
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D003520:Cyclophosphamide / Q000627:therapeutic use; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics*; D003907:Dexamethasone / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014750:Vincristine / Q000627:therapeutic use
D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide