Recent progress in molecular mechanisms of leukemogenesis: the cyclin-dependent kinase 4-inhibitor gene in human leukemias.
In order to clarify the significance of p16 gene (CDKN2) inactivation and its disease specificity among hematopoietic tumors, configurations of the p16 gene as well as those of the adjacent p15 and interferon alpha (IFN alpha) genes were examined in primary hematopoietic tumors. Loss of the p16 gene is frequent in and highly specific to lymphoid tumors among hematopoietic tumors. Gene deletions but not minute mutations should be the predominant mechanism of p16 gene inactivation in these types of tumors. The p16 gene is most frequently deleted among the p16, p15 and IFN alpha genes and thus should be the target of deletions in this locus. Deletions of the p16 gene were frequently observed in tumors carrying chromosome 9p abnormalities while a significant number of cases showed loss of the p16 gene without chromosome 9p abnormalities. So far inactivation of p53 and Rb tumor suppressors have also been found in lymphoid tumors. In our study, we detected homozygous deletions of p16 gene in 20%, loss of Rb protein in 28%, and p53 gene alterations in 8% of lymphoid tumors. Notably, 44% of lymphoid tumors showed inactivation of at least one of the three tumor suppressors, suggesting these tumor suppressors are important for lymphoid tumorigenesis. Inactivations of these tumor suppressors should independently occur in development of lymphoid tumors.
Hirai
H
H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Ogawa
S
S
Hangaishi
A
A
Takahashi
T
T
Kurokawa
M
M
Mitani
K
K
Ueda
R
R
Yazaki
Y
Y
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D019337:Hematologic Neoplasms / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics; D007938:Leukemia / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D017384:Sequence Deletion
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases