State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai Rui Jin Hospital, Shanghai, China.
Blood Cancer J. 2017 Jul 7;7(7):e0. doi: 10.1038/bcj.2017.61.
The activation of oncogenes can reprogram tumor cell metabolism. Here, in diffuse large B-cell lymphoma (DLBCL), serum metabolomic analysis revealed that oncogenic MYC could induce aberrant choline metabolism by transcriptionally activating the key enzyme phosphate cytidylyltransferase 1 choline-α (PCYT1A). In B-lymphoma cells, as a consequence of PCYT1A upregulation, MYC impeded lymphoma cells undergo a mitophagy-dependent necroptosis. In DLBCL patients, overexpression of PCYT1A was in parallel with an increase in tumor MYC, as well as a decrease in serum choline metabolite phosphatidylcholine levels and an International Prognostic Index, indicating intermediate-high or high risk. Both in vitro and in vivo, lipid-lowering alkaloid berberine (BBR) exhibited an anti-lymphoma activity through inhibiting MYC-driven downstream PCYT1A expression and inducing mitophagy-dependent necroptosis. Collectively, PCYT1A was upregulated by MYC, which resulted in the induction of aberrant choline metabolism and the inhibition of B-lymphoma cell necroptosis. Referred as a biomarker for DLBCL progression, PCYT1A can be targeted by BBR, providing a potential lipid-modifying strategy in treating MYC-High lymphoma.
癌基因的激活可以重新编程肿瘤细胞的代谢。在这里，在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中，血清代谢组学分析表明，致癌基因 MYC 可以通过转录激活关键酶磷酸胞苷转移酶 1 胆碱-α (PCYT1A) 诱导异常的胆碱代谢。在 B 淋巴瘤细胞中，由于 PCYT1A 的上调，MYC 阻止淋巴瘤细胞发生依赖于线粒体自噬的坏死性凋亡。在 DLBCL 患者中，PCYT1A 的过度表达与肿瘤 MYC 的增加平行，同时伴随着血清胆碱代谢产物磷脂酰胆碱水平和国际预后指数的降低，表明为中高危或高危。无论是在体外还是体内，降脂生物碱小檗碱 (BBR) 通过抑制 MYC 驱动的下游 PCYT1A 表达和诱导依赖线粒体自噬的坏死性凋亡，表现出抗淋巴瘤活性。总的来说，PCYT1A 被 MYC 上调，导致异常胆碱代谢的诱导和 B 淋巴瘤细胞坏死性凋亡的抑制。作为 DLBCL 进展的生物标志物，PCYT1A 可以被 BBR 靶向，为治疗 MYC 高表达淋巴瘤提供了一种潜在的脂质修饰策略。
