High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.

中文翻译：

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BET溴结构域抑制剂CPI203通过在MYC + / BCL2 +双重打击淋巴瘤的体外和体内模型中下调BFL-1 / A1来克服对ABT-199（venetoclax）的耐药性。

伴有MYC和BCL2和/或BCL6重排的高级B细胞淋巴瘤，通常被称为双击淋巴瘤（DHL），是一种罕见的实体，其特征是Burkitt淋巴瘤与临床上可控制的弥漫性大B细胞之间具有形态学和分子学特征淋巴瘤（DLBCL）。DHL患者通常会经历与标准化学免疫疗法耐药相关的快速发展的临床过程。结果，该实体的预后特别差，中位总生存期低于1年。ABT-199（venetoclax）是一种有效且选择性的BCL-2小分子拮抗剂，最近被批准用于治疗淋巴肿瘤的特定亚型。在这项研究中，我们证明了单药ABT-199可有效替代BCL-2复合物中的BAX，但在大多数MYC + / BCL2 + DHL细胞系和原代培养以及异种移植小鼠模型中，随着时间的推移未能保持显着的抗肿瘤活性。疾病。我们进一步确定BCL2样蛋白BFL-1的积累是参与获得性抗ABT-199的主要机制。值得注意的是，这种现象可以被BET溴结构域抑制剂CPI203抵消，因为基因表达谱将BCL-1编码基因BCL2A1识别为由该化合物调节的最重要的凋亡相关基因之一。在CPI203处理后，MYC和BFL-1的同时下调进一步克服了体内和体外对ABT-199的抗性，在DHL培养物和肿瘤异种移植物中参与了协同的caspase介导的细胞凋亡。