Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Cell Death Dis. 2021 Apr 28;12(5):419. doi: 10.1038/s41419-021-03695-8.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoid malignancy and a highly heterogeneous disease. In this study, we performed whole-genome and transcriptome sequencing, and a genome-wide CRISPR-Cas9-knockout screen to study an activated B-cell-like DLBCL cell line (RC-K8). We identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2. The dependency on CREBBP is associated with a balanced translocation involving EP300, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between CREBBP and EP300 genes, two frequently mutated epigenetic modulators in B-cell lymphoma, was further validated in the previously published CRISPR-Cas9 screens and inhibitor assays. Our study suggests that integration of the unbiased functional screen results with genomic and transcriptomic data can identify both common and unique druggable vulnerabilities in DLBCL and histone acetyltransferases inhibition could be a therapeutic option for CREBBP or EP300 mutated cases.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的侵袭性淋巴恶性肿瘤，也是一种高度异质性疾病。在这项研究中，我们进行了全基因组和转录组测序，以及全基因组 CRISPR-Cas9 敲除筛选，以研究活化 B 细胞样 DLBCL 细胞系（RC-K8）。我们在 RC-K8 中发现了一种独特的遗传必需性模式，包括对 CREBBP 和 MDM2 的依赖性。对 CREBBP 的依赖性与涉及 EP300 的平衡易位有关，导致蛋白的截断形式，缺乏关键的组蛋白乙酰转移酶（HAT）结构域。在之前发表的 CRISPR-Cas9 筛选和抑制剂测定中，进一步验证了 CREBBP 和 EP300 基因（B 细胞淋巴瘤中经常突变的两种表观遗传调节剂）之间的合成致死相互作用。我们的研究表明，将无偏功能筛选结果与基因组和转录组数据相结合，可以确定 DLBCL 中的常见和独特的可用药脆弱性，并且抑制组蛋白乙酰转移酶可能是 CREBBP 或 EP300 突变病例的一种治疗选择。
