Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas
Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas
复制标题
弥漫性大 B 细胞淋巴瘤中 PD-L1 过表达的遗传基础。
DOI：
10.1182/blood-2015-12-686550
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发表时间：
2016-06-16
期刊：
影响因子：
20.3
通讯作者：
Pan-Hammarstrom, Qiang
中科院分区：
文献类型：
--
作者：
Georgiou, Konstantinos;Chen, Longyun;Pan-Hammarstrom, Qiang
弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见和最具侵袭性的 B 细胞淋巴瘤类型之一。易位后原癌基因表达失调，尤其是免疫球蛋白重链基因座 (IGH)，是 DLBCL 的标志之一。通过全基因组测序分析，我们发现 PD-L1/PD-L2 基因座是 DLBCL 中 IGH 的复发易位伴侣。 PIM1 和 TP63 也被确定为 PD-L1/PD-L2 的新型易位伴侣，荧光原位杂交还用于快速筛选扩展的 DLBCL 队列。总的来说，一部分样本被发现受到 PD-L1/PD-L2 基因座增益 (12%)、扩增 (3%) 和易位 (4%) 的影响。 RNA测序数据与免疫组织化学相结合显示，这些细胞遗传学改变与PD-L1表达增加相关，但与PD-L2表达无关。此外，影响PD-L1/PD-L2基因座的细胞遗传学改变在DLBCL的非生发中心B细胞样（非GCB）亚型中更常见。这些发现证明了 DLBCL 中 PD-L1 过度表达的遗传基础，并表明针对 PD-1-PD-L1/PD-L2 轴的治疗可能有益于 DLBCL 患者，尤其是那些属于更具侵袭性的非 GCB 亚型的患者。
Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.