p16ink4a 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, p16ink4a/MTS1/CDKN2 and p15ink4b/MTS2 are both mapped to chromosome 9p21 and inhibit cyclin D-CDK4 and -CDK6 complexes. A feedback regulatory loop involving pRb, p16ink4a, and CDKs seems to regulate G1/S phases transition. p16ink4a and p15ink4b are deleted in high frequency in human cell lines and in some fresh solid tumors. Point mutations of p16ink4a have also been sequenced, especially in familial melanomas and digestive cancers but preferential mechanism of p16ink4a/p15ink4b inactivation seems to be biallelic deletion. In hematological malignancies, homozygous deletions of p16ink4a and p15ink4b 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 p16ink4a deletions are more frequent than p15ink4b deletions, and hemizygous deletions of either p16ink4a and p15ink4b are rare. In ALL an association of homozygous deletions of p16ink4a and p15ink4b, and T-lineage, 9p abnormalities, and prognostic factors was found in some but not all reports. This review presents recent data on p16ink4a and p15ink4b functions and analyses their implications in hematological malignancies.
Quesnel
B
B
Service des maladies du sang CHU Lille, France.
Preudhomme
C
C
Fenaux
P
P
D000328:Adult; D000595:Amino Acid Sequence; D001752:Blast Crisis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002899:Chromosomes, Human, Pair 9; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D005246:Feedback; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases