Molecular Therapy in Hematology and Oncology & Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Cancer Res. 2019 Jun 15;79(12):3125-3138. doi: 10.1158/0008-5472.CAN-18-3438. Epub 2019 Apr 18.
Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation () or B-cell development and activation () and found a number of context-specific dependencies including oncogene addiction in cell lines with / or mutation. The strongest genotype-phenotype association was seen for . MDM4, a negative regulator of , was essential in wild-type (TP53wt) Burkitt lymphoma cell lines. knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
致癌基因 MYC 的激活促进了伯基特淋巴瘤的增殖，但也会诱导肿瘤抑制因子 p53 介导的细胞周期停滞和细胞凋亡，而 p53 在 40%的伯基特淋巴瘤病例中发生突变。为了确定伯基特淋巴瘤中的分子依赖性，我们在 8 种伯基特淋巴瘤细胞系中进行了基于 RNAi 的功能丧失筛选，并整合了非伯基特淋巴瘤 RNAi 筛选和遗传数据。我们鉴定了 76 个对伯基特淋巴瘤至关重要的基因，包括与造血细胞分化（）或 B 细胞发育和激活（）相关的基因，并发现了一些特定于上下文的依赖性，包括在携带 / 或 突变的细胞系中存在癌基因成瘾。与 野生型（TP53wt）伯基特淋巴瘤细胞系中，MDM4（）的负调节剂是必需的。MDM4 基因的敲低激活了 p53，以依赖于 p53 的方式诱导细胞周期停滞，并在异种移植模型中降低肿瘤生长。MDM4-p53 相互作用的小分子抑制仅在 TP53wt 伯基特淋巴瘤细胞系中有效。此外，TP53wt 伯基特淋巴瘤的原始样本经常获得 1q 染色体的增益，包括 基因座，并显示出 MDM4 mRNA 水平的升高。在来自 Achilles 项目的 789 种癌细胞系中，7q 增益与 TP53wt 相关，并且在 216 种代表 19 种癌症实体的细胞系中，在 TP53wt 背景下是必需的。我们的研究结果强调了 p53 作为伯基特淋巴瘤中的肿瘤抑制因子的关键作用，并确定了 MDM4 作为广泛存在 1q 增益的癌症中 的功能性靶点，这是一种可治疗的靶点。意义：靶向 MDM4 以减轻 p53 的降解，可以在伯基特淋巴瘤和其他携带 1q 增益的野生型 p53 的癌症中进行治疗，这是癌症中最常见的拷贝数改变。
