B细胞淋巴瘤中的BCL3重排发生在与不同疾病相关的两个断点簇中。
BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases.
发表日期：2023 Aug 10
作者：
Anna Carbo-Meix, Francesca Guijarro, Luojun Wang, Marta Grau, Romina Royo, Gerard Frigola, Heribert Playa-Albinyana, Marco M Buhler, Guillem Clot, Marti Duran-Ferrer, Junyan Lu, Isabel Granada, Maria-Joao Baptista, Jose-Tomas Navarro, Blanca Espinet, Anna Puiggros, Gustavo Tapia, Laura Bandiera, Gabriella De Canal, Emanuela Bonoldi, Fina Climent, Inmaculada Ribera-Cortada, Mariana Fernandez-Caballero, Esmeralda De la Banda, Janilson Do Nascimento, Alberto Pineda, Dolors Vela, Maria Rozman, Marta Aymerich, Charlotte Syrykh, Pierre Brousset, Miguel Perera, Lucrecia Yanez, Jesus Xavier Ortin, Esperanza Tuset, Thorsten Zenz, James R Cook, Steven H Swerdlow, Jose I Martin-Subero, Dolors Colomer, Estella Matutes, Silvia Bea, Dolors Costa, Ferran Nadeu, Elias Campo
来源：
HAEMATOLOGICA
摘要：
t(14;19)(q32;q13)常将BCL3与IGH相对排列，导致该基因的过度表达。与其他致癌易位相比，BCL3重排（BCL3-R）与广泛的淋巴样肿瘤相关。在这里，我们报告了13例具有BCL3-R的淋巴样肿瘤的整合全基因组序列、转录组和DNA甲基化分析的结果。单碱基分辨率的断点解析显示，这些断点在BCL3的5'（n=9）和3'（n=4）区域以两个不同的生物学和临床实体出现。两个断点都通过IGH基因座的异常类转换复合介导。然而，5'断点（上游）将BCL3与IGH增强子相邻，导致基因过度表达，而3'断点（下游）将BCL3定位在IGH的影响范围之外，并且与其表达无关。上游BCL3-R肿瘤具有未突变的IGHV、三体染色体12和经常出现在CLL中的突变基因，但具有与传统CLL不同的非典型CLL形态、免疫表型、DNA甲基组和表达谱。相反，下游BCL3-R肿瘤是非典型的脾系或淋巴结边缘区淋巴瘤（MZL），具有突变的IGHV、复杂核型和MZL典型的突变基因。其中4种肿瘤中的2种发生了大B细胞淋巴瘤转化。我们设计了一种新型FISH试剂，可以检测出这两个不同的断点，并在17个独立肿瘤中验证了这些发现。总体而言，BCL3-R的上游或下游断点主要与两种具有不同（表观）基因组、表达和临床病理特征的淋巴样肿瘤亚型相关，分别类似于非典型CLL和MZL。
The t(14;19)(q32;q13) often juxtaposes BCL3 with IGH resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3-rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in CLL but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter 4 tumors transformed to a large B-cell lymphoma. We designed a novel FISH assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.