40% 的病例出现弥漫性大 B 细胞淋巴瘤 (DLBCL) 的复发。难治性/复发性 DLBCL (RR-DLBCL) 的护理标准是在自体干细胞移植之前进行铂类治疗；然而，RR-DLBCL 患者的预后仍然很差。因此，为了鉴定影响 DLBCL 中顺铂反应的基因，本研究进行了基于顺铂的全基因组 CRISPR-Cas9 敲除筛选。我们发现 DNA 损伤反应 (DDR) 途径在已识别的 CRISPR 介导的致敏基因敲除中丰富。一致地，无论增殖率如何，核苷酸切除修复基因 XPA 和 ERCC6 的敲除都会使 DLBCL 细胞对铂类药物敏感，从而证明 DDR 对于 DLBCL 顺铂敏感性至关重要。功能分析表明，XPA 和 ERCC6 的缺失会增加 DNA 损伤水平并改变细胞周期分布。有趣的是，我们还鉴定了 BTK，它参与 B 细胞受体信号传导，可以影响顺铂反应。 BTK 敲除增加了 DLBCL 细胞对顺铂的敏感性，联合药物筛选显示 BTK 抑制剂依鲁替尼与低浓度铂类药物具有协同作用。应用本地和外部 DLBCL 队列，我们​​解决了 CRISPR 筛选中识别的基因的临床相关性。 BTK 是最常见的突变基因之一，频率为 3-5%，XPA 和 ERCC6 也发生突变，但频率较低。此外，27-54% 的 DLBCL 诊断样本中存在使细胞对顺铂敏感的通路突变。总之，本研究表明，除 BTK 外，XPA 和 ERCC6 对于 DLBCL 中铂类药物的反应至关重要。

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3-5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27-54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL.