Dreyling M H, Bullinger L, Ott G, Stilgenbauer S, Müller-Hermelink H K, Bentz M, Hiddemann W, Döhner H
Department of Hematology/Oncology, University of Göttingen, Germany.
Cancer Res. 1997 Oct 15;57(20):4608-14.
Mantle cell lymphoma (MCL) has recently become generally accepted as a subentity of malignant lymphomas that is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1. Cyclin D1 forms a complex with cell cycle-dependent kinase (cdk) 4, which inactivates the retinoblastoma protein (pRB) via phosphorylation. However, in transgenic mice, the overexpression of cyclin D1 alone is not sufficient for the development of malignant lymphoma. To determine whether other members of the pRB pathway contribute to the malignant transformation of MCL, we analyzed 37 cases of MCL that were well characterized by morphology, immunophenotype, and/or interphase cytogenetics [detection of t(11;14)(q13;q32)]. Interphase fluorescence in situ hybridization was performed using a cosmid contig (250 kb) of the CDKN2/p16 region (encoding an inhibitor of the cyclin D1/cdk4 complex) and a phage contig (200 kb) of the Rb region. CDKN2/p16 deletion was detected in 15 cases (41%), including 6 homozygous deletions; Rb was deleted in 15 cases (41%), all of which were hemizygous deletions. Nine cases (24%) had deletions of both CDKN2/p16 and Rb. Further analysis of a subset of 17 MCLs revealed a highly significant correlation between CDKN2/p16 deletion and proliferation index, determined by the rate of Ki67 expression (P = 0.014; t test). No significant correlation was found between CDKN2/p16 deletion and the blastoid variant of MCL (P = 0.23; Fisher's test) or between proliferation index and blastoid morphology (P = 0.51; t test). Deletion of Rb did not have any impact on cell proliferation in addition to CDKN2/p16 deletion (P = 0.76; t test). Additional analysis of 13q14 deletions suggests that these deletions may target another gene telomeric to Rb. We conclude that deletion of CDKN2/p16 occurs in approximately one-half of MCLs and is a more relevant indicator of the proliferative features as compared to morphological criteria. In contrast, although deletions of chromosomal band 13q14 are frequent in MCL, inactivation of Rb seems not to be involved in the pathogenesis of MCL.
套细胞淋巴瘤（MCL）最近已被普遍认为是恶性淋巴瘤的一个亚类，其特征为染色体易位t(11;14)(q13;q32)，导致细胞周期蛋白D1过表达。细胞周期蛋白D1与细胞周期依赖性激酶（cdk）4形成复合物，通过磷酸化使视网膜母细胞瘤蛋白（pRB）失活。然而，在转基因小鼠中，单独的细胞周期蛋白D1过表达不足以引发恶性淋巴瘤。为了确定pRB通路的其他成员是否有助于MCL的恶性转化，我们分析了37例经形态学、免疫表型和/或间期细胞遗传学[检测t(11;14)(q13;q32)]充分表征的MCL病例。使用CDKN2/p16区域（编码细胞周期蛋白D1/cdk4复合物的抑制剂）的黏粒重叠群（250 kb）和Rb区域的噬菌体重叠群（200 kb）进行间期荧光原位杂交。在15例（41%）病例中检测到CDKN2/p16缺失，其中包括6例纯合缺失；15例（41%）病例中检测到Rb缺失，均为半合子缺失。9例（24%）病例同时存在CDKN2/p16和Rb缺失。对17例MCL的一个亚组进行进一步分析发现，CDKN2/p16缺失与通过Ki67表达率确定的增殖指数之间存在高度显著相关性（P = 0.014；t检验）。在MCL的母细胞样变异型与CDKN2/p16缺失之间未发现显著相关性（P = 0.23；Fisher检验），在增殖指数与母细胞样形态之间也未发现显著相关性（P = 0.51；t检验）。除CDKN2/p16缺失外，Rb缺失对细胞增殖没有任何影响（P = 0.76；t检验）。对13q14缺失的进一步分析表明，这些缺失可能靶向Rb端粒的另一个基因。我们得出结论，约一半的MCL病例存在CDKN2/p16缺失，与形态学标准相比，它是增殖特征更相关的指标。相比之下，尽管13q14染色体带缺失在MCL中很常见，但Rb失活似乎与MCL的发病机制无关。
