Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China.
Sci Adv. 2023 Mar 29;9(13):eadf0005. doi: 10.1126/sciadv.adf0005.
amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet, how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in -amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of -amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL-2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in -amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
神经母细胞瘤中的扩增导致 MYCN 癌蛋白的异常表达，MYCN 癌蛋白与活性基因结合，促进转录扩增。然而，MYCN 如何协调转录延伸以满足有效的转录扩增，以及哪些延伸机制代表 MYCN 驱动的脆弱性仍有待确定。我们进行了转录延伸因子的靶向筛选，发现超级延伸复合物（SEC）是 -扩增神经母细胞瘤的独特脆弱性。MYCN 直接结合 EAF1 并募集 SEC 以增强连续转录延伸。EAF1 或 AFF1/AFF4（SEC 的另一个核心亚基）的耗竭会导致转录延伸的全面减少，并引发 -扩增神经母细胞瘤细胞的选择性凋亡。联合筛选显示，SEC 抑制与 FDA 批准的 BCL-2 拮抗剂 ABT-199 协同增强治疗效果，部分原因是抑制了 MCL1 的表达，这在 -扩增神经母细胞瘤细胞和患者来源的异种移植瘤中均有体现。这些发现确定了破坏 MYCN-SEC 调节轴作为神经母细胞瘤有前途的治疗策略。
