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Posted by star on 2019-10-14 17:03:14 Hits:161
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In September, scientists from University Hospital Basel, Basel, Ba, Switzerland published their study of mutant JAK2 in Blood.
Mutant JAK2 induces a hitherto unrecognized metabolic phenotype, consisting of hypoglycemia, adipose tissue atrophy and early mortality.
Increased energy demands of JAK2 mutant hematopoietic cells can be targeted by metabolic inhibitors to treat myeloproliferative neoplasms.
Increased energy requirement and metabolic reprograming are hallmarks of cancer cells. Scientists show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2 driven myeloproliferative neoplasms (MPNs). 
They 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. 
Scientists 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.
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