p16(ink4a) gene and hematological malignancies

Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of regulators, the cyclin-dependent CDKkinases (CDKs). Recent studies have identified different CDK inhibitory genes (CDKis), and two of them, p16(ink4a)/MTS1/CDKN2 and p15(ink4b)/MTS2 are both mapped to chromosome 9p21 and inhibit cyclin D-CDK4 and -CDK6 complexes. A feedback regulatory loop involving pRb, p16(ink4a), and CDKs seems to regulate G1/S phases transition. p16(ink4a) and p15(ink4b) are deleted in high frequency in human cell lines and in some fresh solid tumors. Point mutations of p16(ink4a) have also been sequenced, especially in familial melanomas and digestive cancers but preferential mechanism of p16(ink4a)/p15(ink4b) inactivation seems to be biallelic deletion. In hematological malignancies, homozygous deletions of p16(ink4a) and p15(ink4b) occur frequently in acute lymphoblastic leukemia (ALL) (14-40%), lymphoid type blast crisis of chronic myeloid leukemia (CML), and adult T cell leukemia (ATL), but p16(ink4a) deletions are more frequent than p15(ink4b) deletions, and hemizygous deletions of either p16(ink4a) and p15(ink4b), ALL an association of homozygous deletions of p16(ink4a) and p15(ink4b), and T-lineage, 9p abnormalities, and prognostic factors was found in some but not all reports. This review presents recent data on p16(ink4a) and p15(ink4b) functions and analyses their implications in hematological malignancies.