Williams M E, Swerdlow S H, Rosenberg C L, Arnold A
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville 22908.
Leukemia. 1993 Feb;7(2):241-5.
Centrocytic lymphoma is a CD5-positive B-cell neoplasm. Rearrangements at the chromosome 11q13 bcl-1 breakpoint loci are present in the majority of these lymphomas, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain joining genes. Recently, a gene lying approximately 110 kb telomeric of the bcl-1 major translocation cluster breakpoint locus, designated PRAD1, was proposed as a candidate bcl-1 oncogene. Accumulated evidence now indicates that this gene is the postulated bcl-1 oncogene. It encodes a protein with homology to cyclin family proteins designated cyclin D1 (CCND1). In order to determine whether 11q13 translocation breakpoints were present near the PRAD1 coding region in addition to the previously defined bcl-1 sites, we analyzed 27 centrocytic lymphomas by Southern blot using genomic and cDNA probes flanking the first exon of PRAD1. Five samples showed rearrangement at PRAD1 sites. In four of these, the breakpoints could be mapped from approximately one to 25 kb upstream of the first PRAD1 exon; each showed comigration of rearranged PRAD1 and immunoglobulin heavy-chain joining gene bands consistent with the t(11;14)(q13;q32). The fifth case was rearranged with PRAD1 probes only on BamHI-digested DNA, indicating either a point mutation or a polymorphism at this site. This sample also had rearrangement on multiple enzyme digests with the bcl-1 p94PS probe. None of 80 non-centrocytic B-cell neoplasms showed PRAD1 rearrangement. Thus, rearrangement at both bcl-1 and PRAD1 loci is strongly associated with centrocytic lymphoma, and provides a useful molecular marker for classifying this subtype of lymphoma. Furthermore, translocation-induced aberrant expression of the PRAD1 cyclin may lead to deregulated cell cycle control and play an important role in the pathogenesis of centrocytic lymphoma.
中心细胞性淋巴瘤是一种CD5阳性的B细胞肿瘤。由于与14q32免疫球蛋白重链连接基因发生相互易位，在大多数这类淋巴瘤中存在11q13 bcl-1断裂点位点的重排。最近，一个位于bcl-1主要易位簇断裂点位点端粒约110 kb处的基因，命名为PRAD1，被提出作为候选的bcl-1癌基因。目前积累的证据表明该基因就是假定的bcl-1癌基因。它编码一种与细胞周期蛋白家族蛋白具有同源性的蛋白，命名为细胞周期蛋白D1（CCND1）。为了确定除了先前定义的bcl-1位点外，11q13易位断裂点是否存在于PRAD1编码区附近，我们使用位于PRAD1第一个外显子两侧的基因组和cDNA探针，通过Southern印迹法分析了27例中心细胞性淋巴瘤。5个样本显示PRAD1位点发生重排。其中4个样本中，断裂点可定位在PRAD1第一个外显子上游约1至25 kb处；每个样本都显示重排的PRAD1和免疫球蛋白重链连接基因条带共迁移，与t(11;14)(q13;q32)一致。第5例仅在BamHI消化的DNA上与PRAD1探针发生重排，表明该位点存在点突变或多态性。该样本在使用bcl-1 p94PS探针进行多种酶消化时也发生了重排。80例非中心细胞性B细胞肿瘤均未显示PRAD1重排。因此，bcl-1和PRAD1位点的重排与中心细胞性淋巴瘤密切相关，为该淋巴瘤亚型的分类提供了一个有用的分子标志物。此外，易位诱导的PRAD1细胞周期蛋白异常表达可能导致细胞周期调控失调，并在中心细胞性淋巴瘤的发病机制中起重要作用。
