Aberrant methylation of the major breakpoint cluster region in chronic myeloid leukemia.
Isolated hypomethylated sites exist in the major breakpoint cluster region (M-bcr) where most Philadelphia chromosome (Ph) breakpoints are located. Twenty of 50 (40%) chronic myeloid leukemia (CML) patients were found to have aberrant hypermethylation of these sites on the rearranged M-bcr when compared with control marrows. The aberrancy correlated strongly with M-bcr breakpoint location; 19 of 20 cases had breakpoints located 5' of the M-bcr Sca I site, and 28 of 30 cases with normal M-bcr methylation had breakpoints located 3' of the M-bcr Sca I site. Sequence analysis of the Ph M-bcr breakpoints failed to find an M-bcr nucleotide position that delineated the transition between abnormally and normally methylated cases, indicating that the translocation of a critical M-bcr sequence was not responsible for the methylation abnormality. In 3 of 8 CML patients, cells without the t(9;22) were found to have abnormally methylated, unrearranged M-bcrs. The data indicate that abnormally methylated rearranged M-bcrs are present in CML cases with Ph breakpoints 5' of the M-bcr Sca I site and that the M-bcr in Ph- cells of patients with CML may also be abnormally methylated.
Litz
C E
CE
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis.
Vos
J A
JA
Copenhaver
C M
CM
D000483:Alleles; D001483:Base Sequence; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008745:Methylation; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics*; D010677:Philadelphia Chromosome; D012150:Polymorphism, Restriction Fragment Length; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D015183:Restriction Mapping; D014178:Translocation, Genetic
D017931:DNA Primers; D004273:DNA, Neoplasm; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr