N-acetylcysteine and Vitamin C stimulate MYC binding to EGR1 and selectively stimulate apoptosis in B cell lymphoma. N-acetylcysteine and Vitamin C stimulate MYC binding to EGR1 and selectively stimulate apoptosis in B cell lymphoma

Refractory and relapsed B cell lymphomas are often driven by MYC, a difficult-to-target oncogene due to its central role in normal transcription. Here we report that N-acetylcysteine (NAC) and vitamin C (VitC)—in doses that reduce reactive oxygen species levels levels—trigger apoptosis in human B lymphoma cells with high MYC expression. Intraperitoneal NAC and VitC injections dose-dependently reduced tumor growth in xenograft experiments, and combined NAC/VitC administration stopped tumor growth. Knockdown of MYC restored tumor growth in the presence of NAC and VitC and switching-on MYC expression in B cells rendered them sensitive to the compounds. The compounds stimulated MYC binding to Early growth response protein 1 (EGR1)—an interaction found to require Cys132 of MYC—which reduced MYC binding to promotors of cell cycle genes and increased binding to apoptotic genes; and thus, switched MYC’s transcriptional output from cell cycle to apoptosis gene expression. Short-term combined NAC/VitC administration into λMYC transgenic mice, an endogenous mouse model of B cell lymphoma, after tumor onset increased survival fourfold; and life-long oral administration of NAC and VitC stimulated apoptosis and reduced B cell progenitors in the spleen and measurably increased survival. The results provide a rationale with mechanistic understanding for evaluating the therapeutic efficacy of NAC and VitC in patients with MYC-driven B cell lymphoma. Overall design: 2 cell lines, 3 treatments

复发难治性B细胞淋巴瘤多由MYC原癌基因（MYC oncogene）驱动，而MYC原癌基因因其在正常转录过程中的核心调控作用，成为极具挑战性的靶向靶点。本研究证实，以可有效降低活性氧簇水平的剂量给予N-乙酰半胱氨酸（N-acetylcysteine, NAC）与维生素C（vitamin C, VitC），可诱导高表达MYC的人B淋巴瘤细胞发生凋亡。异种移植瘤模型实验显示，腹腔注射NAC与VitC可呈剂量依赖性抑制肿瘤生长，而二者联合给药可完全阻滞肿瘤增殖。在NAC与VitC共同处理的条件下，敲低MYC可恢复肿瘤生长能力；反之，在B细胞中激活MYC表达，则可使细胞对该类化合物产生敏感性。该类化合物可促进MYC与早期生长应答蛋白1（Early growth response protein 1, EGR1）的结合，该相互作用依赖于MYC蛋白的Cys132位点。此结合事件会减少MYC与细胞周期基因启动子的结合，同时增加其与凋亡相关基因的结合，进而将MYC的转录调控方向从细胞周期基因表达转向凋亡相关基因表达。在λMYC转基因小鼠——一种内源性B细胞淋巴瘤小鼠模型——中，于肿瘤发生后短期联合给予NAC与VitC，可使小鼠生存期延长至原来的4倍；而终身口服NAC与VitC，则可诱导脾脏中的B细胞前体发生凋亡并减少其数量，且可显著延长小鼠生存期。本研究结果为评估MYC驱动型B细胞淋巴瘤患者应用NAC与VitC的治疗疗效提供了基于机制阐释的科学依据。整体实验设计：2株细胞系，3种处理方案。