GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GCB-DLBCL cells. Interestingly, GNA13 negatively regulates BCL2 expression in GCB-DLBCL cells in a palmitoylation-dependent manner. Consistently, BCL2 inhibitors were found to be effective in killing GNA13-deficient GCB-DLBCL cells in a cell-based chemical screen. Furthermore, we demonstrate that inactivating GNA13 by targeting its palmitoylation enhanced the sensitivity of GCB-DLBCL to the BCL2 inhibitor. These studies indicate that the loss-of-function mutation of GNA13 is a biomarker for BCL2 inhibitor therapy of GCB-DLBCL and that GNA13 palmitoylation is a potential target for combination therapy with BCL2 inhibitors to treat GCB-DLBCL with wild-type GNA13.

GNA13，编码异源三聚体 G 蛋白的 G 蛋白 α 亚基之一，转导 G 蛋白偶联受体 (GPCR) 的信号，在生发中心 B 细胞样弥漫性大 B 细胞淋巴瘤 (GCB-DLBCL) 中经常发生突变预后结果。由于 GNA13 的“不可成药”性质，无法针对这些患者进行靶向治疗。在这项研究中，我们发现 GNA13 的棕榈酰化不仅调节其质膜定位，还调节 GNA13 的稳定性。GNA13 在 GCB-DLBCL 细胞中的肿瘤抑制功能是必不可少的。有趣的是，GNA13 以棕榈酰化依赖性方式负调节 GCB-DLBCL 细胞中 BCL2 的表达。一致地，在基于细胞的化学筛选中发现 BCL2 抑制剂可有效杀死缺乏 GNA13 的 GCB-DLBCL 细胞。此外，我们证明通过靶向其棕榈酰化灭活 GNA13 增强了 GCB-DLBCL 对 BCL2 抑制剂的敏感性。这些研究表明，GNA13 的功能丧失突变是 BCL2 抑制剂治疗 GCB-DLBCL 的生物标志物，而 GNA13 棕榈酰化是与 BCL2 抑制剂联合治疗用野生型 GNA13 治疗 GCB-DLBCL 的潜在靶点。