DNA methylation patterns at relapse in adult acute lymphocytic leukemia.
OBJECTIVE
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.


METHODS
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.
Garcia-Manero
Guillermo
G
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. ggarciam@mdanderson.org
Bueso-Ramos
Carlos
C
Daniel
Jerry
J
Williamson
Jason
J
Kantarjian
Hagop M
HM
Issa
Jean-Pierre J
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology; D018797:Cell Cycle Proteins; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D016147:Genes, Tumor Suppressor; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D014408:Biomarkers, Tumor; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins