Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-Hodgkin's lymphomas

Abstract

The tumor suppressor genes p16INK4A and p15INK4B map to the 9p21 chromosomal locus and are either homozygously deleted or mutated in a wide range of human cancer cell lines and tumors. Although chromosome 9 abnormalities have been described in non-Hodgkin's lymphomas (NHLs), to date, the mutational status of these genes has not been determined for these malignancies. A total of five cell lines and 75 NHLs were examined for homozygous deletions or point mutations in the coding regions of both the p15 and p16 genes using Southern blot and/or polymerase chain reaction-single-strand conformation polymorphism analyses. Homozygous deletions of either the p16 gene or both the p15 and p16 genes were observed in one diffuse large B-cell lymphoma cell line and two uncultured lymphomas consisting of one large B-cell and one mixed T-cell lymphoma. In contrast, point mutations were not detected in either the cell lines or lymphomas. These results indicate that the rate of alterations in the p15 and p16 genes is low for lymphomas, but loss of p16 and/or p15 may be involved in the development of some lymphomas.

Codeletion of CDKN2 and MTAP genes in a subset of non‐Hodgkin's lymphoma may be associated with histologic transformation from low‐grade to diffuse large‐cell lymphoma

“…In a fashion similar to the present study, two of their DLCL cases with homozygous CDKN2A deletions were transformed lymphomas. Gombart et al (1995) found CDKN2A gene deletion in two of 84 (2%) NHL cases, one of which was a transformed lymphoma. Similarly, CDKN2A deletions have been described in three NHL cell lines established from cases that had undergone transformation from lowto high-grade disease (Stranks et al, 1995).…”

“…Although CDKN2A deletions occur in a significant percentage of acute lymphoblastic leukemias and high-grade lymphomas, the different subsets of NHL that may harbor CDKN2A deletions have not been well characterized (Ogawa et al, 1994;Okuda et al, 1995;Stranks et al, 1995). Gombart et al (1995) found only two cases of NHL with CDKN2A deletions in a series of 75 cases, and other authors could not detect any CDKN2A deletion in NHL (Quesnel et al, 1994;Fizzotti et al, 1995). Koduru et al (1995) recently reported that deletion of CDKN2A and CDKN2B occurred in about 15% of diffuse large-cell tumors examined.…”

Analysis of p18INK4C in adult T‐cell leukaemia and non‐Hodgkin's lymphoma

“…Cyclin-dependent kinase inhibitors (CDKIs) bind to specific cyclin-dependent kinases (CDKs) or CDK-cyclin complexes, thereby resulting in arrest of the cell cycle. We have investigated the inactivation of several CDKIs in ATL and NHL, and have found that deletions of the p15 INK4B and p16 INK4A genes were frequent (27%; 10/37 cases) in ATL and infrequent in NHL (4%; 3/75 cases) (Gombart et al, 1995); alterations of the p27 KIP1 gene were rare in ATL (5%; 2/42 cases) and NHL (1%; 1/72 cases) ; and no abnormalities were found in the p19 INK4D gene in either ATL or NHL (Shiohara et al, 1996). Further studies of ATL have shown that inactivation of p16 INK4A could be caused by either deletions or point mutations (Uchida et al, 1996).…”

Apoptosis resistance and response to chemotherapy in primary nodal diffuse large B‐cell lymphoma

“…In this review we discuss the possible mechanisms leading to intrinsic resistance to apoptosis and provide an explanation why strong differences in apoptosis sensitivity between DLBCL are observed. Subsequently we will focus on how differences in this intrinsic apoptosis resistance provide an explanation for the variable response to combination chemotherapy and how this can be used for further therapy tailoring.The INK4a/ARF locus [42,43] is an important mediator of oncogene-dependant p53 induced apoptosis in which p14ARF is involved [44]. BMI-1, belonging to the Polycomb-group (PcG) of genes which are important regulators…”

“…The INK4a/ARF locus [42,43] is an important mediator of oncogene-dependant p53 induced apoptosis in which p14ARF is involved [44]. BMI-1, belonging to the Polycomb-group (PcG) of genes which are important regulators…”