PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma.
PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma.
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DOI：
10.1172/jci153436
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Riches, John C.
中科院分区：
文献类型：
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作者：
D'Avola, Annalisa;Legrave, Nathalie;Tajan, Mylene;Chakravarty, Probir;Shearer, Ryan L.;King, Hamish W.;Kluckova, Katarina;Cheung, Eric C.;Clear, Andrew J.;Gunawan, Arief S.;Zhang, Lingling;James, Louisa K.;MacRae, James, I;Gribben, John G.;Calado, Dinis P.;Vousden, Karen H.;Riches, John C.
从葡萄糖合成丝氨酸是支持健康和恶性细胞中细胞增殖的关键代谢途径。尽管如此，这方面的代谢在老年中心生物学和病理学中的作用尚不清楚。在这里，我们进行了一个全面的表征丝氨酸合成途径的作用，在生发中心B细胞和淋巴瘤来自这些细胞。我们证明功能性丝氨酸合成途径的上调是B细胞活化和生发中心反应的代谢标志。磷酸甘油酸脱氢酶（PHGDH），在这一途径中的第一个和限速酶的抑制，导致有缺陷的germinate形成和受损的高亲和力抗体的生产。此外，丝氨酸合成相关酶的过度表达是生发中心B细胞来源淋巴瘤的特征，高水平表达预示着弥漫性大B细胞淋巴瘤的总生存率降低。抑制PHGDH诱导淋巴瘤细胞凋亡，减少疾病进展。这些发现确立了PHGDH作为体液免疫的关键参与者和淋巴瘤的临床相关靶点。
The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate-limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B cell–derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells, reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.