B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Mar 20

PMID 29551267

Citations 76

Authors

Gang Xiao

Lai N Chan

Lars Klemm

Daniel Braas

Zhengshan Chen

Huimin Geng

Qiuyi Chen Zhang

Ali Aghajanirefah

Kadriye Nehir Cosgun

Teresa Sadras

Jaewoong Lee

Tamara Mirzapoiazova

Ravi Salgia

Thomas Ernst

Andreas Hochhaus

Hassan Jumaa

Xiaoyan Jiang

David M Weinstock

Thomas G Graeber

Markus Muschen

Affiliations

Soon will be listed here.

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.

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