Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
|Number of pages||15|
|State||Published - Nov 21 2019|
Bibliographical noteFunding Information:
This work was supported by grants from the Swiss National Science Foundation (31003A-147016/1 and 31003A_166613), SystemsX.ch (Medical Research and Development Grant 2014/266), and the Swiss Cancer League (KLS-2950-02-2012 and KFS-3655-02-2015) (R.C.S.) and by grants from the Forschungsfonds der Universität Basel (DMM 2039) and Krebsliga Beider Basel (KLbB-4486) (T.N.R.). Stable isotope resolved metabolomics was performed with the support of the Resource Facility for Stable Isotope Resolved Metabolomics, funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant 1U24DK097215-01A1 (T.W.-M.F.), and the Markey Cancer Center grant P30CA177558 supporting metabolomics instrumentation (B. M. Evers).
Conflict-of-interest disclosure: T.R. is a full-time employee of Novartis Pharma AG; R.C.S. has consulted for and received honoraria from Novartis, Shire, and Baxalta; and S.K. reports research funding from Novartis, AOP Orphan Pharmaceuticals AG, and Bristol-Myers Squibb as well as consultancy honoraria and travel reimbursements from Novartis, AOP Orphan Pharmaceuticals AG, and Bristol-Myers Squibb. The remaining authors declare no competing financial interests.
© 2019 by The American Society of Hematology.
ASJC Scopus subject areas
- Cell Biology