Protein Phosphatase 2A Is Essential for B-cell Tumor Redox Homeostasis

Protein phosphatases are critical mediators of key signal transduction pathways; however, little is known about therapeutically targeting protein phosphatases in cancer. Having recently shown that B cell–derived leukemias are dependent upon the protein phosphatases PTEN and INPP5D, Xiao and colleagues investigated the role of protein phosphatase 2A (PP2A), which controls autoimmunity and has been shown to be a tumor suppressor in other cancers, in B-cell malignancies. Cre-mediated deletion of PP2A scaffold subunit Aα (Ppp2r1a) in mice revealed that PP2A function is critical for B cell, but not myeloid cell, development and for B-cell acute lymphoblastic leukemia (B-ALL) survival. PP2A depletion in B-ALL cells reduced the activation of FOXO1 and FOXO3a, both of which drive the antioxidant transcriptional program, and significantly reduced B-ALL leukmogenesis in vivo. Further, PP2A deletion resulted in increased glucose consumption and decreased expression of enzymes that drive the antioxidant pentose phosphate pathway (PPP) in B cell but not myeloid leukemia cells. Mass spectrometry analyses showed that PP2A is essential for driving glucose-derived carbon from glycolysis to the PPP by negatively regulating the phosphorylation of the bifunctional 6-phosphofructo-2-kinase/fructose 2,6 biphosphatase 2 (Pfkfb2) to promote the phosphatase activity of PFKFB2, resulting in glucose carbon utilization by the PPP and not glycolysis. B lymphoid transcription factors repressed the expression of rate-limiting PPP enzymes to regulate PPP activity and PP2A dependency in B cells and in B-ALL patient–derived xenografts; similarly, human B-cell tumors exhibit decreased expression of rate-limiting PPP enzymes. Treatment with a PP2A inhibitor or genetic ablation of PPP2R1A resulted in decreased growth of human B-ALL in vitro and increased survival in vivo. These results characterize the role of PP2A in B-cell malignancies and suggest that PP2A and enzymes that promote the metabolic switch from glycolysis to the PPP can be therapeutically targeted in these cancers.

Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, et al. B-cell-specific diversion of glucose carbon utilization reveals a unique vulnerability in B cell malignancies. Cell 2018;173:470–84.e18.

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