Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, DLBCL patients with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene-expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2 targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced cytotoxicity in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug-resistance mechanisms mediated by upregulation of MCL-1 and RAS/RAF/mTOR pathways. In summary, these findings support sub-classification of DLBCL/HGBCL with dual MYC/TP53 alterations which demonstrates distinct pathobiological features and dismal survival with standard therapy therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.

中文翻译：

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MYC/TP53双重改变的侵袭性B细胞淋巴瘤显示出不同的临床病理学特征和对新型靶向药物的反应

弥漫性大 B 细胞淋巴瘤 (DLBCL) 是侵袭性 B 细胞淋巴瘤的主要类型。在当前的 WHO 淋巴瘤分类中，具有 MYC/BCL2 双重打击 (DH) 的高级别 B 细胞淋巴瘤 (HGBCL) 代表了一个在标准免疫化疗后预后不佳的独特实体。然而，TP53 突变是否与 MYC 异常（MYC 重排和/或 Myc 蛋白过表达）协同导致 HGBCL 样生物学和预后尚未得到很好的研究。在这项研究中，具有 MYC/TP53 异常的 DLBCL 患者表现出较差的临床结果、高级形态和不同的基因表达特征。为了确定针对这一独特 DLBCL 亚群的更有效疗法，在具有 MYC/TP53 双重改变或 HGBCL-MYC/BCL2-DH 的 DLBCL 细胞中研究了新型 MYC/TP53/BCL-2 靶向药物。无论 MYC/BCL2/TP53 状态如何，BET 抑制剂 INCB057643 都能有效抑制 DLBCL/HGBCL 细胞的细胞活力并诱导细胞凋亡。将 INCB057643 与 MDM2-p53 抑制剂 DS3032b 联合使用可显着增强无 TP53 突变的 HGBCL-DH 中的细胞毒性，而与 BCL-2 抑制剂 venetoclax 联合使用在有或无并发 TP53 突变的 DLBCL/HGBCL 细胞中显示出有效的治疗协同作用。反相蛋白阵列揭示了 INCB057643、DS3032b 和 venetoclax 诱导细胞周期停滞和细胞凋亡以及抑制 AKT/MEK/ERK/mTOR 通路的协同分子作用，以及由 MCL-1 上调介导的潜在耐药机制和 RAS/RAF/mTOR 通路。总之，这些发现支持具有双重 MYC/TP53 改变的 DLBCL/HGBCL 的子分类，这表明标准治疗具有不同的病理生物学特征和令人沮丧的存活率，因此需要额外的靶向治疗。启示：临床和药理学研究表明，将伴随 TP53 突变和 MYC 异常的 DLBCL 识别为精准肿瘤学实践所必需的独特实体。