Abstract 368: B-lymphoid transcriptional repression of the pentose phosphate pathway reveals a unique therapeutic vulnerability of B cell malignancies
Authors: Xiao Gang , Chen Zhengshan , Chan Lai N. , Braas Daniel , Graeber Thomas G. , Geng Huimin , Jumaa Hassan , Jiang Xiaoyan , Müschen Markus 
Published: August 2018

Introduction 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 tumor suppressor in multiple types of cancer, our genetic studies revealed an unexpected lineage-specific dependency on PP2A in a broad range of B-cell malignancies.

Results PP2A regulates glycolysis rate and balances energy supply against anti-oxidant protection of B-cells through the pentose-phosphate pathway (PPP). In contrast to robust PPP-activity in other hematopoietic lineages, B-lymphoid transcription factors (PAX5, IKZF1) restrict PPP-activity by transcriptional repression of G6PD and other rate-limiting PPP enzymes. Constitutively low PPP-activity and limited capacity to balance redox fluctuations cause a unique dependency on PP2A in B-cell tumors. Pharmacological ablation of PP2A and PPP-activity identify this pathway as a novel lineage-specific therapeutic target in a broad range of B-cell malignancies.

Highlights • Conditional deletion of Ppp2r1a, the central scaffold assembling the PP2A holoenzyme, induces acute cell death of early and mature B-cells but does not affect other hematopoietic lineages. • PP2A redirects glucose carbon utilization from glycolysis to the PPP to mitigate oxidative stress. • B-cell malignancies exhibit constitutively low PPP activity, owing to B-cell-specific transcriptional repression of G6PD and other rate-limiting PPP enzymes. • Transcriptional repression of PPP activity in B-cells represents the mechanistic basis for the unique dependency of B-cell malignancies on PP2A. • Small molecule inhibitors of PP2A and G6PD act synergistically and overcome conventional drug-resistance in B-cell tumors.

Summary Genetic lesions of PP2A are frequent in solid tumors and myeloid leukemia, but not in B-cell malignancies. Unlike other 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 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 repression of PPP activity, 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 novel 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.

Citation Format: Gang Xiao, Zhengshan Chen, Lai N. Chan, Daniel Braas, Thomas G. Graeber, Huimin Geng, Hassan Jumaa, Xiaoyan Jiang, Markus Müschen. B-lymphoid transcriptional repression of the pentose phosphate pathway reveals a unique therapeutic vulnerability of B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 368.