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

T Nageswara Rao, N Hansen, J Hilfiker, S Rai, JM Majewska, D Lekovic, D Gezer, N Andina, S Galli, T Cassel, F Geier, J Delezie, R Nienhold, H Hao-Shen, C Beisel, S Di Palma, Sarah Dimeloe, J Trebicka, D Wolf, M GassmannTW Fan, AN Lane, C Handschin, S Dirnhofer, N Kroger, Christoph Hess, T Radimerski, S Koschmieder, VP Cokic, RC Skoda

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13 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)1832-1846
Number of pages15
JournalBlood
Volume134
Issue number21
Early online date11 Sept 2019
DOIs
Publication statusPublished - 21 Nov 2019

Bibliographical note

© 2019 by The American Society of Hematology.

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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