Sonoki T, Harder L, Horsman D E, Karran L, Taniguchi I, Willis T G, Gesk S, Steinemann D, Zucca E, Schlegelberger B, Solé F, Mungall A J, Gascoyne R D, Siebert R, Dyer M J
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, United Kingdom.
Blood. 2001 Nov 1;98(9):2837-44. doi: 10.1182/blood.v98.9.2837.
Chromosomal translocation t(6;14)(p21.1;q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6;14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5(+) DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. Comparison with the genomic sequence for chromosome 6p21.1 showed breakpoints approximately 59 and 73.5 kilobases 5' of the cyclin D3 (CCND3) gene with no other identifiable transcribed sequences in the intervening region. Although Southern blotting with derived genomic 6p21.1 probes failed to detect other rearrangements, fluorescent in situ hybridization assays, using BAC (bacterial artificial chromosome) clones spanning and flanking the CCND3 locus, along with probes for IGH confirmed localization of 6p21.1 breakpoints within the same region, as well as fusion of the CCND3 and IGH loci. Furthermore, in all cases, high-level expression of CCND3 was demonstrated at RNA and/or protein levels by Northern and Western blotting and by immunohistochemistry. These data implicate CCND3 as a dominant oncogene in the pathogenesis and transformation in several histologic subtypes of mature B-cell malignancies with t(6;14)(p21.1;q32.3) and suggest that CCND3 overexpression seen in about 10% of DLBCL cases may have a genetic basis.
染色体易位t(6;14)(p21.1;q32.3)不仅在骨髓瘤和浆细胞白血病中，而且在弥漫性大B细胞非霍奇金淋巴瘤（B-NHL）（弥漫性大B细胞淋巴瘤[DLBCL]）和脾绒毛状淋巴细胞淋巴瘤（SLVL）中均有报道，是一种罕见但反复出现的事件；然而，目标基因的性质尚未确定。本研究在3例转化型结外边缘区B-NHL、1例SLVL和1例低度B细胞淋巴增殖性疾病中发现了t(6;14)(p21.1;q32.3)。在第六例CD5(+) DLBCL中，在没有细胞遗传学可检测到的变化的情况下，通过分子克隆鉴定出了这种易位。使用长距离反向聚合酶链反应方法克隆了两个染色体易位断点。与6号染色体p21.1的基因组序列比较显示，断点位于细胞周期蛋白D3（CCND3）基因5'端约59和73.5千碱基处，中间区域没有其他可识别的转录序列。尽管用衍生的基因组6p21.1探针进行Southern印迹未能检测到其他重排，但使用跨越CCND3基因座及其侧翼的BAC（细菌人工染色体）克隆以及IGH探针进行的荧光原位杂交分析证实，6p21.1断点位于同一区域内，以及CCND3和IGH基因座的融合。此外，在所有病例中，通过Northern和Western印迹以及免疫组织化学在RNA和/或蛋白质水平上证实了CCND3的高水平表达。这些数据表明CCND3是具有t(6;14)(p21.1;q32.3)的几种成熟B细胞恶性肿瘤组织学亚型发病机制和转化中的主要癌基因，并表明在约10%的DLBCL病例中看到的CCND3过表达可能有遗传基础。
