CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.This article is highlighted in the In This Issue feature, p. 327.

中文翻译：

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选择性抑制 HDAC3 可靶向合成脆弱性并激活淋巴瘤中的免疫监视。


CREBBP 突变在 B 细胞淋巴瘤中高度复发，并且会使其组蛋白乙酰转移酶 (HAT) 结构域失活或截短蛋白质。在此，我们表明这两类突变会对表观基因组产生不同程度的破坏，其中 HAT 突变更为严重，并且与较差的临床结果相关。受 CREBBP 突变干扰的基因是 BCL6-HDAC3 肿瘤抑制复合物的直接靶标。因此，我们发现 HDAC3 选择性抑制剂可逆转 CREBBP 突变体异常表观遗传编程，从而导致：(i) 通过诱导 BCL6 靶基因（如 CDKN1A）抑制淋巴瘤细胞的生长，以及 (ii) 由于诱导 BCL6 而恢复免疫监视-抑制干扰素途径和抗原呈递基因。通过重新激活这些基因，暴露于 HDAC3 抑制剂可以恢复肿瘤浸润淋巴细胞以 MHC I 类和 II 类依赖性方式杀死 DLBCL 细胞的能力，并在体内同基因模型中与 PD-L1 阻断产生协同作用。因此，HDAC3 抑制代表了一种针对 CREBBP 突变淋巴瘤的新型基于机制的免疫表观遗传疗法。意义：我们利用不同类型 CREBBP 突变的分子特征来定义通过选择性抑制 HDAC3 来靶向这些突变的合理方法。这代表了一种有吸引力的治疗途径，可以针对 CREBBP 突变细胞中的合成漏洞，同时促进抗肿瘤免疫。 327.