Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.
The recently identified cyclin-dependent kinase inhibitor p15INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p15INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2'-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-beta. These results suggest that p15INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.
Herman
J G
JG
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Jen
J
J
Merlo
A
A
Baylin
S B
SB
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002648:Child; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003110:Colonic Neoplasms / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004247:DNA / Q000097:blood / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry / Q000302:isolation & purification; D015226:Dinucleoside Phosphates / Q000032:analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics; D008214:Lymphocytes; D008297:Male; D008745:Methylation; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D012016:Reference Values; D015183:Restriction Mapping; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004247:DNA; D004273:DNA, Neoplasm; D015226:Dinucleoside Phosphates; D025521:Tumor Suppressor Proteins; C493966:CDKN2B protein, human; C015772:CpG dinucleotide