B-cell-specific diversion of glucose carbon utilization reveals a unique vulnerability in B cell malignancies
Open accessAbstract
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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Induced loss of Aα decreased PP2A-C expression and resulted in acute cell death in a B-cell lineage-specific manner.
“Induced loss of Aα apparently decreased PP2A-C expression as well, and resulted in acute cell death in a B-cell lineagespecific manner.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Decreased expression of enzymes driving the pentose phosphate pathway was attributed to increased Pfkfb2 Ser483 phosphorylation, which promotes its 6-phosphofructo-2-kinase activity over its fructose 2,6-bisphosphatase activity.
“a decrease in expression of enzymes driving the pentose phosphate pathway was observed that was attributed to an increased phosphorylation of Pfkfb2 (Ser483), which promotes its 6-phosphofructo-2-kinase activity over its fructose 2,6-bisphosphatase activity.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Conditional Aα knockout in the B-cell lineage did not affect normal pro-B and early pre-B cell numbers, but severely diminished cell numbers once pre-BCR-dependent stages were reached, resulting in barely detectable mature B-cells.
“Conditional KO of Aα in the B-cell lineage (at pro-B cell stage) did not affect normal pro-B and early pre-B cell numbers, but severely diminished cell numbers once the pre-B-Cell Receptor (BCR)-dependent stages were reached, resulting in barely detectable mature B-cell numbers [75].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
This change in enzyme activity/specificity driving the pentose phosphate pathway was causally linked to the phenotype, as TIGAR overexpression rescued Aα-depletion-induced cell death.
“This change in enzyme activity/specificity, driving the pentose phosphate pathway, was causally linked to the phenotype, as overexpression of TIGAR, a TP53-induced glycolysis regulatory phosphatase that harbors a fructose 2,6 bisphosphatase activity, could rescue the Aα-depletion-induced cell death.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Increased cell death correlated with moderate increases in ERK and AKT phosphorylation, increased mTOR-S6 kinase signaling, inactivation of FoxO1 and FoxO3a, and decreased expression of antioxidant FoxO target genes.
“The increased cell death correlated with moderate increases in ERK and AKT phosphorylation, increased activation of mTOR-S6 kinase signaling, inactivation of FoxO1 and -3a, and decreased expression of antioxidant, FoxO target genes (e.g.Cat).”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Overexpression of catalase rescued cell death, implicating reactive oxygen species in the cell death mechanism.
“Overexpression of catalase rescued cell death, inferring the involvement of Reactive Oxygen Species (ROS) in the cell death mechanism.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Aα knockout cells showed increased glycolysis without changes in mitochondrial respiration, alongside an amplified mTORC1 pathway.
“Alongside an amplified mTORC1 pathway, the Aα KO cells showed increased glycolysis in the absence of any changes in mitochondrial respiration.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
Increased cell death upon Aα deficiency was also demonstrated in several B-cell lineage-specific cancer models in vitro and in vivo, but not in myeloid lineage cancer models.
“increased cell death upon Aα deficiency was also demonstrated in several cell models of B-cell lineage-specific cancers in vitro and in vivo, but not in cancer models of the myeloid lineage”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [75]
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Physiologic functions of PP2A: Lessons from genetically modified mice
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- Authors
- Xiao, G., Chan, L. N., Klemm, L., Braas, D., Chen, Z., Geng, H., Zhang, Q. C., Aghajanirefah, A., Cosgun, K. N., Sadras, T., Lee, J., Mirzapoiazova, T., Salgia, R., Ernst, T., Hochhaus, A., Jumaa, H., Jiang, X., Weinstock, D. M., Graeber, T. G., & Müschen, M.
- Affiliations
- City of Hope (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Jena University Hospital (DE)
- BC Cancer Agency (CA)
- Harvard University (US)
- Corresponding author
- Xiao, Gang
- Müschen, Markus
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 173
- Issue
- 2
- Pages
- 470-484.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6284818
- OpenAlex
- W2790448745
- Cited by
- 129
- References
- 45
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 20 · 2023: 14 · 2022: 13 · 2021: 20 · 2020: 12 · 2019: 17 · 2018: 10
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH/NCI (R35CA197628, R01CA137060, R01CA157644, R01CA172558, R01CA213138)
- Wellcome Trust
- Leukemia and Lymphoma (WT101880, LLS-1479-11)
- Howard Hughes Medical Institute (HHMI-55108547)
- Norman and Sadie Lee Foundation
- Dr. Ralph and Marian Falk Medical Research Trust
- Cancer Research Institute
- California Institute for Regenerative Medicine (DISC2-10061)
- Deutsche Forschungsgemeinschaft (SFB1074, P10)
- ERC (694992)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- B-cell malignancies, protein phosphatase 2A, pentose phosphate pathway, glycolysis, glucose metabolism, oxidative stress, glucose-6-phosphate dehydrogenase, PAX5, IKZF1, tumor suppressor, metabolic vulnerability, small molecule inhibitors, redox homeostasis
- MeSH terms
- Animals, B-Lymphocytes, Carbon, Cell Survival, Glucose, Glucosephosphate Dehydrogenase, Glycolysis, Humans, Mice, Inbred C57BL, Pentose Phosphate Pathway, Transcription, Genetic, Mice, Inbred NOD, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Cell Line, Tumor, Mice, Ikaros Transcription Factor, PAX5 Transcription Factor, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein Phosphatase 2
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