Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia.
Hypermethylation in cancer often occurs in CpG islands that span the promoter regions of tumor suppressor genes. However, it is not clear if hypermethylation is limited to single target genes or if multiple genes are simultaneously methylated. To understand the extent of aberrant de novo methylation, we have analyzed the methylation pattern of a number of tumor-related genes in leukemia from the same cohort of patients. We used bisulfite genomic sequencing to characterize the methylation pattern of the CpG islands associated with the calcitonin, estrogen receptor, E-cadherin, p15, p16, Rb, GST-Pi, and HIC1 genes in the bone marrow from 9 normal and 20 patients with acute myeloid leukaemia (AML). All of the normal control samples were essentially unmethylated for each of the eight tumor-related genes studied. In contrast, 19 of 20 (95%) of the AML patients had an abnormal methylation pattern in at least one gene, and 15 of 20 (75%) had abnormal methylation patterns in two or more of the target genes. We conclude that there is a general deregulation of CpG island methylation in leukemia and that hypermethylation is not limited to single genes, but a number of genes are methylated concurrently. Moreover, the subset of genes that are commonly methylated in leukemia appear to be cancer type specific.
Melki
J R
JR
Kanematsu Laboratories, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Vincent
P C
PC
Clark
S J
SJ
D000208:Acute Disease; D000328:Adult; D000368:Aged; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D002116:Calcitonin / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis; D019175:DNA Methylation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005796:Genes; D016161:Genes, Retinoblastoma; D019942:Genes, p16; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D015820:Cadherins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C096870:Hic1 protein, mouse; D007527:Isoenzymes; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D002116:Calcitonin; D004248:DNA (Cytosine-5-)-Methyltransferases; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase