Potential role for concurrent abnormalities of the cyclin D1, p16(CDKN2) and p15(CDKN2B) genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519)

被引:98
作者
Jadayel, DM
Lukas, J
Nacheva, E
Bartkova, J
Stranks, G
DeSchouwer, PJJC
Lens, D
Bartek, J
Dyer, MJS
Kruger, AR
Catovsky, D
机构
[1] ROYAL MARSDEN HOSP,CANC RES INST,ACAD DEPT HAEMATOL & CYTOGENET,SUTTON,SURREY,ENGLAND
[2] DANISH CANC SOC,DIV CANC BIOL,COPENHAGEN,DENMARK
[3] UNIV CAMBRIDGE,DEPT HAEMATOL,CAMBRIDGE CB2 1TN,ENGLAND
[4] TRELISKE HOSP,TRURO,CORNWALL,ENGLAND
关键词
cell cycle; cyclin D1; p16; p15; mantle cell lymphoma; TUMOR-SUPPRESSOR GENE; G1 PHASE PROGRESSION; HUMAN BREAST-CANCER; RETINOBLASTOMA-PROTEIN; KINASE-ACTIVITY; G(1) CONTROL; P16; GENE; LEUKEMIAS; EXPRESSION; REARRANGEMENT;
D O I
10.1038/sj.leu.2400555
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16(CDKN2) and p15(CDKN2B) 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, p16(CDKN2) and p15(CDKN2B) genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16(CDKN2) 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, 17p11, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16(CDKN2) and p15(CDKN2B) 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 (RE) 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 PRE kinase. Electroporation of wild-type p16(CDKN2) arrested the Granta 519 cells in G1, consistent with the p16(CDKN2) 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 p16(CDKN2), an effect which could be prevented by ectopic expression of p16(CDKN2). Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16(CDKN2) and p15(CDKN2B) 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 RE tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
引用
收藏
页码:64 / 72
页数:9
相关论文
共 57 条
  • [21] LUKAS J, 1994, ONCOGENE, V9, P707
  • [22] LUKAS J, 1994, ONCOGENE, V9, P2159
  • [23] LUKAS J, 1995, ONCOGENE, V10, P2125
  • [24] LUKAS J, 1995, CANCER RES, V55, P4818
  • [25] RETINOBLASTOMA-PROTEIN-DEPENDENT CELL-CYCLE INHIBITION BY THE TUMOR-SUPPRESSOR P16
    LUKAS, J
    PARRY, D
    AAGAARD, L
    MANN, DJ
    BARTKOVA, J
    STRAUSS, M
    PETERS, G
    BARTEK, J
    [J]. NATURE, 1995, 375 (6531) : 503 - 506
  • [26] Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas
    Maelandsmo, GM
    Florenes, VA
    Hovig, E
    Oyjord, T
    Engebraaten, O
    Holm, R
    Borresen, AL
    Fodstad, O
    [J]. BRITISH JOURNAL OF CANCER, 1996, 73 (08) : 909 - 916
  • [27] PREPARATION OF PEROXIDASE - ANTI-PEROXIDASE (PAP) COMPLEXES FOR IMMUNOHISTOLOGICAL LABELING OF MONOCLONAL-ANTIBODIES
    MASON, DY
    CORDELL, JL
    ABDULAZIZ, Z
    NAIEM, M
    BORDENAVE, G
    [J]. JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 1982, 30 (11) : 1114 - 1122
  • [28] D-TYPE CYCLIN-DEPENDENT KINASE-ACTIVITY IN MAMMALIAN-CELLS
    MATSUSHIME, H
    QUELLE, DE
    SHURTLEFF, SA
    SHIBUYA, M
    SHERR, CJ
    KATO, JY
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (03) : 2066 - 2076
  • [29] MELO JV, 1988, CLIN EXP IMMUNOL, V73, P23
  • [30] 5' CPG ISLAND METHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL SILENCING OF THE TUMOR-SUPPRESSOR P16/CDKN2/MTS1 IN HUMAN CANCERS
    MERLO, A
    HERMAN, JG
    MAO, L
    LEE, DJ
    GABRIELSON, E
    BURGER, PC
    BAYLIN, SB
    SIDRANSKY, D
    [J]. NATURE MEDICINE, 1995, 1 (07) : 686 - 692