Data Entry: Please note that the research database will be replaced by UNIverse by the end of October 2023. Please enter your data into the system https://universe-intern.unibas.ch. Thanks

Login for users with Unibas email account...

Login for registered users without Unibas email account...

 
JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4514743
Author(s) Nageswara Rao, Tata; Hansen, Nils; Hilfiker, Julian; Rai, Shivam; Majewska, Julia-Magdalena; Lekovic, Danijela; Gezer, Deniz; Andina, Nicola; Galli, Serena; Cassel, Teresa; Geier, Florian; Delezie, Julien; Nienhold, Ronny; Hao-Shen, Hui; Beisel, Christian; Di Palma, Serena; Dimeloe, Sarah; Trebicka, Jonel; Wolf, Dominik; Gassmann, Max; Fan, Teresa W.-M.; Lane, Andrew N.; Handschin, Christoph; Dirnhofer, Stefan; Kröger, Nicolaus; Hess, Christoph; Radimerski, Thomas; Koschmieder, Steffen; Cokic, Vladan P.; Skoda, Radek C.
Author(s) at UniBasel Handschin, Christoph
Year 2019
Title JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
Journal Blood
Volume 134
Number 21
Pages / Article-Number 1832-1846
Mesh terms Animals; Hematopoietic Stem Cells, metabolism; Humans; Janus Kinase 2, genetics; Mice; Mutation; Myeloproliferative Disorders, metabolism
Abstract 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.
Publisher American Society of Hematology
ISSN/ISBN 0006-4971 ; 1528-0020
edoc-URL https://edoc.unibas.ch/72123/
Full Text on edoc No
Digital Object Identifier DOI 10.1182/blood.2019000162
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/31511238
ISI-Number WOS:000499645800010
Document type (ISI) Journal Article
 
   

MCSS v5.8 PRO. 0.335 sec, queries - 0.000 sec ©Universität Basel  |  Impressum   |    
28/03/2024