PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma
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Annalisa D'Avola Nathalie Legrave Mylene Tajan Probir Chakravarty Ryan L Shearer Hamish W King Katarina Kluckova Eric Cheung Andrew J Clear Arief S Gunawan Lingling Zhang Louisa K James James Macrae John G Gribben Dinis Calado Karen Vousden John RichesAbstract
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 demonstrated 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.
Journal details
Volume 132
Issue number 9
Pages e153436
Available online
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Publisher website (DOI) 10.1172/JCI153436
Europe PubMed Central 35316216
Pubmed 35316216
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- Tumour Biology
- Stem Cells
- Signalling & Oncogenes
- Model Organisms
- Metabolism
- Infectious Disease
- Immunology
- Human Biology & Physiology
- Genome Integrity & Repair
- Genetics & Genomics
- Developmental Biology
- Computational & Systems Biology
- Chemical Biology & High Throughput
- Cell Biology
- Biochemistry & Proteomics
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