University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
Center for Integrated Oncology, University of Cologne, Cologne, Germany.
Blood Cancer Discov. 2021 Jan;2(1):70-91. doi: 10.1158/2643-3230.BCD-19-0059.
Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in , as well as copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a and -driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased expression, compared to GCB-DLBCL. experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring and aberrations.
基于基因表达谱，弥漫性大 B 细胞淋巴瘤 (DLBCL) 可细分为生发中心 B 细胞样 (GCB) 和激活 B 细胞样 (ABC) DLBCL。ABC-DLBCL 中最常见的两种基因组异常是 和 拷贝数增益的突变。在这里，我们采用免疫表型、RNA-Seq 和全外显子测序来描述一种 ABC-DLBCL 的 和 驱动的小鼠模型。我们表明，这种模型类似于人类 ABC-DLBCL 的特征。我们进一步证明了我们的 ABC-DLBCL 小鼠模型对 BCL2 的可操作性依赖性。这种 BCL2 依赖性在人类 ABC-DLBCL 细胞系中也可检测到。此外，与 GCB-DLBCL 相比，人类 ABC-DLBCL 显示出更高的 表达水平。在我们的 ABC-DLBCL 模型中进行的 实验表明，venetoclax 和 RMP1-14 的联合使用显著增加了淋巴瘤荷瘤动物的总生存率，表明该联合治疗可能是携带 和 异常的特定人类 ABC-DLBCL 病例的一种可行选择。
