JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

Nageswara Rao, Tata and Hansen, Nils and Hilfiker, Julian and Rai, Shivam and Majewska, Julia-Magdalena and Lekovic, Danijela and Gezer, Deniz and Andina, Nicola and Galli, Serena and Cassel, Teresa and Geier, Florian and Delezie, Julien and Nienhold, Ronny and Hao-Shen, Hui and Beisel, Christian and Di Palma, Serena and Dimeloe, Sarah and Trebicka, Jonel and Wolf, Dominik and Gassmann, Max and Fan, Teresa W.-M. and Lane, Andrew N. and Handschin, Christoph and Dirnhofer, Stefan and Kröger, Nicolaus and Hess, Christoph and Radimerski, Thomas and Koschmieder, Steffen and Cokic, Vladan P. and Skoda, Radek C.. (2019) JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms. Blood, 134 (21). pp. 1832-1846.

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Official URL: https://edoc.unibas.ch/72123/

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Increased energy requirement and metabolic reprograming 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, while 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 wildtype 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 MPN. 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 MPN and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPN.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Associated Research Groups > Pharmakologie (Handschin)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
UniBasel Contributors:Handschin, Christoph
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:28 Jul 2020 14:12
Deposited On:09 Jul 2020 13:51

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