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

TY - JOUR

T1 - JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

AU - Rao, Tata Nageswara

AU - Hansen, Nils

AU - Hilfiker, Julian

AU - Rai, Shivam

AU - Majewska, Julia-Magdalena

AU - Leković, Danijela

AU - Gezer, Deniz

AU - Andina, Nicola

AU - Galli, Serena

AU - Cassel, Teresa

AU - Geier, Florian

AU - Delezie, Julien

AU - Nienhold, Ronny

AU - Hao-Shen, Hui

AU - Beisel, Christian

AU - Di Palma, Serena

AU - Dimeloe, Sarah

AU - Trebicka, Jonel

AU - Wolf, Dominik

AU - Gassmann, Max

AU - Fan, Teresa W-M

AU - Lane, Andrew N

AU - Handschin, Christoph

AU - Dirnhofer, Stefan

AU - Kröger, Nicolaus

AU - Hess, Christoph

AU - Radimerski, Thomas

AU - Koschmieder, Steffen

AU - Čokić, Vladan P

AU - Skoda, Radek C

N1 - © 2019 by The American Society of Hematology.

PY - 2019/11/21

Y1 - 2019/11/21

N2 - 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.

AB - 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.

U2 - 10.1182/blood.2019000162

DO - 10.1182/blood.2019000162

M3 - SCORING: Journal article

C2 - 31511238

VL - 134

SP - 1832

EP - 1846

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 21

ER -