| Literature DB >> 29551267 |
Gang Xiao1, Lai N Chan2, Lars Klemm2, Daniel Braas3, Zhengshan Chen2, Huimin Geng4, Qiuyi Chen Zhang2, Ali Aghajanirefah2, Kadriye Nehir Cosgun2, Teresa Sadras2, Jaewoong Lee2, Tamara Mirzapoiazova2, Ravi Salgia2, Thomas Ernst5, Andreas Hochhaus5, Hassan Jumaa2, Xiaoyan Jiang6, David M Weinstock7, Thomas G Graeber3, Markus Müschen8.
Abstract
B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.Entities:
Keywords: B cell malignancies; G6PD; PP2A; glucose metabolism; lineage-specific vulnerability; redox homeostasis; transcriptional repression
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Year: 2018 PMID： 29551267 PMCID： PMC6284818 DOI： 10.1016/j.cell.2018.02.048
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582