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)
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)
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DOI：
10.1038/sj.leu.2400555
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发表时间：
1997-01-01
期刊：
影响因子：
11.4
通讯作者：
Catovsky, D
中科院分区：
文献类型：
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作者：
Jadayel, DM;Lukas, J;Catovsky, D
在B细胞非霍奇金淋巴瘤（B-NHL）中，细胞周期调控基因cyclin D1、p16（CDKN 2）和p15（CDKN 2 B）的缺失已被证实。我们描述了一个新的B-NHL细胞系（Granta 519），与并发异常的细胞周期蛋白D1，p16（CDKN 2）和p15（CDKN 2B）基因。一个独立的临床病例套细胞NHL（Mc-NHL）伴随细胞周期蛋白D1的过度表达，并删除p16（CDKN 2）基因也被确定，这表明这种组合的致癌畸变是一个病理生理的贡献NHL病例的子集。细胞系Granta 519的可用性促进了对这一概念的更深入的功能研究，该细胞系来源于高级别NHL的病例并具有成熟的B细胞免疫表型。细胞遗传学分析鉴定出易位t（11;14）（q13;q32）和涉及染色体9 p22、13 p21、17 p11和18 q21的复杂重排。分子分析鉴定了细胞周期蛋白D1 mRNA的过表达和p16（CDKN 2）和p15（CDKN 2B）基因的双等位基因缺失。为了阐明这些遗传异常对Granta 519细胞G1期控制的影响，研究了细胞周期蛋白D/视网膜母细胞瘤（RE）途径主要组分的水平和功能。细胞周期蛋白D1在D型细胞周期蛋白中占主导地位，与细胞周期蛋白依赖性激酶（Cdk）Cdk 4而不是Cdk 6形成丰富的复合物，并且免疫沉淀的细胞周期蛋白D1/Cdk 4全酶具有PRE激酶活性。电穿孔野生型p16（CDKN 2）逮捕的Granta 519细胞在G1期，与p16（CDKN 2）的损失，作为一个生物学相关的事件在肿瘤的多步演变，并与功能pRB的表达。这些不同的异常，NHL细胞的细胞周期失调的直接合作，建议G1期加速诱导过表达的细胞周期蛋白D1在控制乳腺癌细胞系缺乏p16（CDKN 2），这种影响可以防止异位表达p16（CDKN 2）。两者合计，这些数据表明，同时过表达的细胞周期蛋白D1和功能消除的p16（CDKN 2）和p15（CDKN 2B）可能表征某些情况下套细胞NHL，合作的异常可能提供一个生长优势的肿瘤细胞通过更有效的灭活RE肿瘤抑制。这种可能性的进一步临床病理学研究是必要的。
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.