Boston Children's Hospital, Boston, United States.
Dana-Farber Cancer Institute, Boston, United States.
Elife. 2019 Mar 12;8:e44161. doi: 10.7554/eLife.44161.
Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor loss, which also require expression of the E2 ubiquitin-conjugating enzyme, . Our studies identify a synthetic lethal relationship between -deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.
肾髓质癌（RMC）是一种罕见且致命的肾癌，发生于携带镰状细胞特征的非洲裔患者中。我们已经开发了忠实的患者衍生的 RMC 模型，通过全基因组测序，我们在一个等位基因中发现了功能丧失的内含子融合事件，同时另一个等位基因缺失。这些模型的生化和功能特征表明，RMC 的存活需要 的缺失。通过 RNAi 和 CRISPR-Cas9 功能丧失遗传筛选和小分子筛选的整合，我们发现泛素-蛋白酶体系统（UPS）在 RMC 中是必需的。UPS 的抑制会导致 cyclin B1 的持续积累，从而导致 G2/M 期阻滞。这些观察结果扩展到了携带 缺失的癌症，这些癌症也需要 E2 泛素连接酶的表达 。我们的研究确定了 -缺陷型癌症与依赖 UPS 之间的合成致死关系，这为使用蛋白酶体抑制剂进行基于机制的临床试验提供了基础。
