Yao Haidong, Chen Xue, Wang Ting, Kashif Muhammad, Qiao Xi, Tüksammel Elin, Larsson Lars-Gunnar, Okret Sam, Sayin Volkan I, Qian Hong, Bergo Martin O
Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden; Department of Plastic and Cosmetic Surgery, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan 430 030, China.
Cell Rep. 2023 Aug 29;42(8):112961. doi: 10.1016/j.celrep.2023.112961. Epub 2023 Aug 9.
Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.
难治性和复发性B细胞淋巴瘤通常由难以靶向的致癌基因MYC驱动。在此，我们报告高MYC表达在正常氧化应激水平下刺激增殖并保护B淋巴瘤细胞免于凋亡，并且包括N-乙酰半胱氨酸（NAC）和维生素C（VitC）在内的化合物通过降低氧化应激诱导凋亡。NAC和VitC注射有效减少高MYC表达的淋巴瘤细胞中的肿瘤生长，但对低MYC表达的细胞无效。MYC敲低赋予肿瘤对NAC和VitC的抗性，而MYC激活使B细胞对这些化合物敏感。从机制上讲，NAC和VitC通过MYC的Cys117刺激MYC与EGR1结合，将其转录输出从细胞周期转变为凋亡基因表达。这些结果确定了一种氧化还原控制的机制，用于MYC在维持增殖和防止凋亡中的作用，为评估NAC或VitC在MYC驱动的B细胞淋巴瘤患者中的潜在治疗原理提供了依据。
