The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

MYC致癌基因是生长和增殖的有力驱动因素，但也会使细胞对细胞凋亡敏感，从而限制其致癌潜力。MYC 诱导多种生物合成程序和原代细胞过度表达MYC对谷氨酰胺戒断高度敏感，表明 MYC 诱导的细胞凋亡敏感性可能是由于代谢/能量供应和需求的不平衡。在这里，我们表明 MYC 提高了全局转录和翻译，即使在没有谷氨酰胺的情况下，也揭示了没有相应供应的代谢需求。从 MRC-5 成纤维细胞中去除谷氨酰胺会耗尽关键的三羧酸 (TCA) 循环代谢物，并与 MYC 激活相结合，导致 AMP 积累和核苷酸分解代谢，表明能量应激。进一步的分析表明，谷氨酰胺通过 TCA 循环能量学而不是天冬酰胺生物合成支持生存能力，并且 TCA 循环抑制在体内对 MYC 驱动的淋巴瘤产生肿瘤抑制。总之，