Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells

Abstract

The cyclin-dependent kinase inhibitors known as p15, p16, p18 and p19 have been suggested as candidates for tumor suppressor genes. The main genetic alterations are deletions (bior monoallelic) or 5Ј CpG island methylation of p15 and p16; very few cases or cell lines had p18 or p19 deletions or hypermethylation. Hypermethylation and homozygous deletions of tumor suppressor genes establish a new paradigm of inactivation by lack of expression, in contrast to the previously identified tumor suppressors which are predominantly inactivated by point mutations followed by loss of the wild-type allele. Here, the literature data on alterations of this gene family in more than 4700 primary cases of leukemia or lymphoma and some 320 continuous leukemia-lymphoma cell lines are summarized. Among hematopoietic malignancies, the highest frequencies of p15 del and p16 del were seen in acute lymphoblastic leukemia (ALL) (Ͼ30%) with striking rates in T-ALL (Ͼ50%), but also high rates in B cell precursor (BCP)-ALL (Ͼ20%); the rates of deletions in chronic lymphoid leukemia (CLL), multiple myeloma, acute and chronic myeloid leukemia (AML and CML), and myelodysplastic syndromes (MDS) were rather low, only some B cell and T cell lymphomas showed increased frequencies. Results are quite different with regard to the second mode of inactivation, hypermethylation of the promoter region. Here, p15 is most often inactivated, at particularly high frequencies in the disorders lacking any p15/p16 deletions: 40-80% p15 met in AML, MDS and multiple myeloma. Also p15 met rates in BCPand T-ALL cases were high (c. 40%). There is controversy concerning the prognostic impact of p15 and p16 aberrations with some studies describing a significant correlation between inactivation of these genes and poor prognosis, while most others did not detect any prognostic relevance, at least in pediatric ALL; there may be a worse prognosis for adults with B or T cell lymphomas. Despite the small number of cases studied, paired sequential analyses suggested that disease progression is associated with loss of p15/p16 activity in a certain percentage of adult patients. p15 del /p16 del and p15 met /p16 met were also detected in the large panel of leukemia-lymphoma cell lines studied. In general, the results in cell lines reproduce the data seen in primary cells with the important difference that the rates of p15/p16 inactivation are clearly higher in the cultured cells compared with the freshly explanted cells. Retrovirus-or electroporation-mediated ectopic gene transfer of p16 wild-type into p16-deficient cell lines led to growth inhibition, arrest in G 1 (without apoptosis) and occasionally to differentiation, suggesting that the malignant phenotype of p16 −/− cell lines can, at least partially, be reversed by restoring p16 gene expression. A striking inverse correlation between the absence of p16 (due to deletion) and presence of wild-type retinoblastoma gene was observed in cell lines confirming a common growth suppressor pathway; no comparable relationship of p1...

p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice

“…Although Tal1 induces leukemia in mice, it does so after a long latency revealing that additional genetic events are required (Condorelli et al, 1996;Kelliher et al, 1996). Analysis of the INK4A/ARF locus in human T-ALL patients has revealed frequent homozygous deletion of exon 2, the exon common to both p16 INK4A and p14 ARF genes (Hebert et al, 1994;Cayuela et al, 1995Cayuela et al, , 1996Drexler, 1998;Gardie et al, 1998;Ferrando et al, 2002). Other T-ALL patients also exhibit alterations in the INK4A/ ARF locus that affect either p16 INK4A or p14 ARF only.…”

The INK4 family of cell cycle inhibitors in cancer

“…Screens of human tumors for genetic alterations (including mutations, deletions, rearrangements, or promoter hypermethylation and silencing), and the creation and analyses of knock-out mice, clearly implicate the INK4a/ARF locus, as an important target in cancer. In contrast, the other INK4 or CIP/ KIP loci do not appear to be involved in the etiology of cancer (Hirama and Koe er, 1995;Hall and Peters, 1996;Drexler, 1998). Several excellent reviews on CKIs (Harper and Elledge, 1996;Nakayama and Nakayama, 1998) and the roles of p16 INK4a (Ruas and Peters, 1998) and the INK4a/ARF locus in cancer have been recently published (Sherr, 1998;Sharpless and DePinho, 1999).…”

p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

“…Consequently, gene methylation was a major occurrence among p16 gene alterations in our study, which is in accord with previous reports. [10][11][12][13][14][15][16] Gene deletion is another means of p16 gene silencing, but has been rare in MALT lymphomas. 32,33 We attempted to detect p16 gene deletions using seven microsatellite markers, 16,34 however, most of the cases were not amplifiable or informative.…”

“…The activity of cyclinD-CDK4/6 complexes is subjected to additional levels of regulation, including the association with CDK inhibitors. 10 The p16/INK4a gene, mapped to 9q21, encodes for nuclear protein that can block cell cycle progression by effectively inhibiting the kinase activity of CDK4/6, thereby exerting a negative control on cell proliferation. p16 gene has been considered as a tumor-suppressor gene, and among CDK inhibitors, only p16 gene is frequently silenced in a variety of tumors by epigenetic or genetic abnormalities including promoter CpG methylation and less frequently, allelic loss and gene mutation.…”

“…p16 gene has been considered as a tumor-suppressor gene, and among CDK inhibitors, only p16 gene is frequently silenced in a variety of tumors by epigenetic or genetic abnormalities including promoter CpG methylation and less frequently, allelic loss and gene mutation. 10,11 In lymphoid malignancies, p16 gene silencing, mainly induced by gene methylation, is frequently found in Hodgkin and non-Hodgkin lymphomas, [12][13][14] and has been associated with tumor progression. [15][16][17][18][19] However, it has also been suggested that the methylation of this gene is one of the early events in the development of lymphoid malignancies.…”