Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8⁺ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.

尽管选择性 HDAC3 抑制在具有CREBBP突变的淋巴瘤亚群中显示出希望，但野生型肿瘤通常表现出耐药性。在这里，使用无偏倚的全基因组 CRISPR 筛选，我们确定GNAS敲除 (KO) 是耐药淋巴瘤细胞对 HDAC3 抑制的敏化剂。从机制上讲， GNAS KO 诱导的致敏独立于典型的 G 蛋白活性，但出乎意料地由病毒拟态相关干扰素 (IFN) 反应介导，其特征是 TBK1 和 IRF3 激活、双链 RNA 形成和转座元件 (TE) 表达。 GNAS KO 还与 HDAC3 抑制协同作用，增强 CD8 ⁺ T 细胞诱导的细胞毒性。此外，我们在人类淋巴瘤患者中观察到，低GNAS表达与高基线 TE 表达和上调的 IFN 信号传导相关，并且在组蛋白修饰、mRNA 加工和转录调控方面与GNAS KO 具有共同的被破坏的生物活性。总的来说，我们的研究结果在淋巴瘤中的 HDAC3 抑制和病毒拟态之间建立了前所未有的联系。我们建议低GNAS表达作为一种潜在的生物标志物，反映了淋巴瘤临床治疗中病毒拟态启动对 HDAC3 抑制的增强反应，特别是CREBBP野生型病例。