瑞金新知速遞 第284期|任瑞寶研究員發現GNA13調節GCB型瀰漫性大B細胞淋巴瘤對BCL2抑制劑敏感性

[Abstract]

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.

【中文摘要】

作為主要的抑癌基因，GNA13在生發中心B細胞樣瀰漫性大B細胞淋巴瘤（GCB-DLBCL）和Burkitt淋巴瘤（Burkitt’s lymphoma, BL）中均存在高頻失活突變。由GNA13編碼的蛋白質GNA13是一個棕櫚醯化蛋白，其失活可削弱S1PR2-GNA13-ARHGEF1軸對AKT的負調控作用，促使淋巴結生發中心的B細胞遷移至外周血，並最終誘發腸道淋巴瘤。在本項工作中，作者發現GNA13的抑癌作用完全依賴於其氨基端（N端）的棕櫚醯化修飾：GNA13棕櫚醯化位點突變造成其膜錨定缺陷，促進GCB-DLBCL細胞增殖，同時改變蛋白穩定性。有意思的是，抑制GNA13的棕櫚醯化可顯著激活PI3K-AKT信號通路並上調BCL-2的表達。高通量藥物篩選結果顯示，GNA13失活的DLBCL細胞系對BCL-2抑制劑（尤其是ABT-199）敏感性增強，而GNA13野生型的細胞系則相對耐藥；研究人員進一步發現，在體內及體外抑制GNA13棕櫚醯化的同時聯用BCL2抑制劑，可大幅提高GCB-DLBCL對BCL2抑制劑的敏感性，顯著抑制腫瘤生長。以上研究提示，發生失活突變（如棕櫚醯化突變）的GNA13是GCB-DLBCL群體應用BCL2抑制劑的生物標誌物，而GNA13的棕櫚醯化則有潛力成為GNA13野生型患者應用BCL2抑制劑的靶點。