Involvement of INK4 Family Cyclin-dependent-kinase Inhibitor Genes in Hematological Malignancies
Recent studies of the biochemistry of cell cycle progression have led to the discovery of a group of small proteins called cyclindependent-kinase inhibitors (CDK-I), CDK-Is. These proteins interact with and inhibit the activity of cyclin/cyclin-dependent-kinases complexes and act as a brake on cell cycle progression. Some of these small proteins such as p16 and pl5 genes appear to behave as tumor suppressor genes in a variety of neoplasms, including hematological malignancies. Numerous studies have been published regarding the inactivation of these genes in human malignant neoplasms. In hematological malignancies, homozygous deletion is a frequent mechanism of inactivation of pl6 and p15 in acute lymphocytic leukemias with immature blasts, particularly in those with T-cell phenotypes. In this manuscript, we have presented the results of investigations performed in the Hematopathology Section of the Laboratory of Pathology, National Cancer Institute and summarized the existing literature concerning the abnormalities pl6 and/or pl5 genes in hematological malignancies and solid tumors. We have also reviewed literature that suggests that hypermethylation of the 5'CpG island of the pl6 gene may also result in transcriptional silencing of the gene and lead to its functional inactivation. The combined data suggests that the CDK-I genes play an important role in the genesis of acute lymphoid leukemias as well as in the genesis of other types of solid tumors, through at least three different mechanisms of gene inactivation. Nonetheless, additional studies are necessary to further define the biologic role of these genes in human cancers, and to elucidate the clinical consequences of alterations of these genes in human cancers.