title: Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519).
abstract: Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
authors.affiliation: Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Royal Marsden Hospital Sutton, Surrey, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Jadayel
authors.forename: J
authors.initials: J
authors.lastname: Lukas
authors.forename: E
authors.initials: E
authors.lastname: Nacheva
authors.forename: J
authors.initials: J
authors.lastname: Bartkova
authors.forename: G
authors.initials: G
authors.lastname: Stranks
authors.forename: P J
authors.initials: PJ
authors.lastname: De Schouwer
authors.forename: D
authors.initials: D
authors.lastname: Lens
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.forename: M J
authors.initials: MJ
authors.lastname: Dyer
authors.forename: A R
authors.initials: AR
authors.lastname: Kruger
authors.forename: D
authors.initials: D
authors.lastname: Catovsky
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D019938:Cyclin D1; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1