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

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.

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…47 Therefore, while mTORC1 activation must be transient to support the GC reaction, constitutive mTORC1 activation seems to be highly supportive of lymphoma survival. 125 High expression levels of the key PPP enzyme G6PD in DLBCL patients associate with poor prognosis. 125 High expression levels of the key PPP enzyme G6PD in DLBCL patients associate with poor prognosis.…”

“…(Figure 3). 125 Furthermore, pharmacological inhibition of PP2A or G6PD induces cell death in the DLBCL cell line OCI-Ly10, with a strong synergistic effect of combined inhibition. 125 Furthermore, pharmacological inhibition of PP2A or G6PD induces cell death in the DLBCL cell line OCI-Ly10, with a strong synergistic effect of combined inhibition.…”

“…125 High expression levels of the key PPP enzyme G6PD in DLBCL patients associate with poor prognosis. 125 In normal B cells, PPP is normally kept low through the action of the transcription factors PAX5 and IKZF1 that specifically repress G6PD and other PPP enzymes. 125 PP2A inhibition or PP2A plus G6PD inhibition also increases survival of mice engrafted with primary human DLBCL cells.…”

Plasma cells: You are what you eat

“…BM: bone marrow. 39,40 Mutating PAX5 alleviates some of these metabolic constraints, thereby allowing pre-B ALL cells to divide indefinitely. 36,37 Despite this critical role in establishing and maintaining B cell identity, Pax5 is frequently mutated in B cell malignancies.…”

Metabolic underpinnings of leukemia pathology and treatment

“…In a subsequent report, serine/threonine phosphatase 2A (PP2A) was revealed to be essential to B cell tumors with a primary function of shifting glucose metabolism from glycolysis to the PPP to generate reducing equivalents (ie, NADPH) that counteract oxidative stress (Figure ) . Normal B cells possess low PPP activity due to the repressed expression of PPP enzymes by PAX5 and IKZF1 (Figure ) .…”