Prikaz osnovnih podataka o dokumentu
JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
dc.creator | Rao, Tata Nageswara | |
dc.creator | Hansen, Nils | |
dc.creator | Hilfiker, Julian | |
dc.creator | Rai, Shivam | |
dc.creator | Majewska, Julia-Magdalena | |
dc.creator | Leković, Danijela | |
dc.creator | Gezer, Deniz | |
dc.creator | Andina, Nicola | |
dc.creator | Galli, Serena | |
dc.creator | Cassel, Teresa | |
dc.creator | Geier, Florian | |
dc.creator | Delezie, Julien | |
dc.creator | Nienhold, Ronny | |
dc.creator | Hao-Shen, Hui | |
dc.creator | Beisel, Christian | |
dc.creator | Di Palma, Serena | |
dc.creator | Dimeloe, Sarah | |
dc.creator | Trebicka, Jonel | |
dc.creator | Wolf, Dominik | |
dc.creator | Gassmann, Max | |
dc.creator | Fan, Teresa W. -M. | |
dc.creator | Lane, Andrew N. | |
dc.creator | Handschin, Christoph | |
dc.creator | Dirnhofer, Stefan | |
dc.creator | Kroeger, Nicolaus | |
dc.creator | Hess, Christoph | |
dc.creator | Radimerski, Thomas | |
dc.creator | Koschmieder, Steffen | |
dc.creator | Čokić, Vladan | |
dc.creator | Skoda, Radek C. | |
dc.date.accessioned | 2021-04-20T13:01:26Z | |
dc.date.available | 2021-04-20T13:01:26Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.uri | http://rimi.imi.bg.ac.rs/handle/123456789/919 | |
dc.description.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. | en |
dc.publisher | Amer Soc Hematology, Washington | |
dc.relation | Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [31003A-147016/1, 31003A_166613] | |
dc.relation | SystemsX.ch (Medical Research and Development Grant) [2014/266] | |
dc.relation | Swiss Cancer League [KLS-2950-02-2012, KFS-3655-02-2015] | |
dc.relation | Forschungsfonds der Universitat Basel [DMM 2039] | |
dc.relation | Krebsliga Beider Basel [KLbB-4486] | |
dc.relation | Resource Facility for Stable Isotope Resolved Metabolomics - National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [1U24DK097215-01A1] | |
dc.relation | Markey Cancer Center grant [P30CA177558] | |
dc.relation | United States Department of Health & Human Services, National Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA177558, P30CA177558, P30CA177558, P30CA177558, P30CA177558, P30CA177558, P30CA177558, P30CA17755] | |
dc.relation | United States Department of Health & Human Services, National Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [U24DK097215, U24DK097215] | |
dc.rights | openAccess | |
dc.source | Blood | |
dc.title | JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms | en |
dc.type | article | |
dc.rights.license | ARR | |
dc.citation.epage | 1846 | |
dc.citation.issue | 21 | |
dc.citation.other | 134(21): 1832-1846 | |
dc.citation.rank | aM21 | |
dc.citation.spage | 1832 | |
dc.citation.volume | 134 | |
dc.identifier.doi | 10.1182/blood.2019000162 | |
dc.identifier.fulltext | http://rimi.imi.bg.ac.rs/bitstream/id/717/916.pdf | |
dc.identifier.pmid | 31511238 | |
dc.identifier.scopus | 2-s2.0-85074985153 | |
dc.identifier.wos | 000499645800010 | |
dc.type.version | publishedVersion |