title: Targeting glutamine metabolism in myeloproliferative neoplasms.
abstract: JAK2(V617F) mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2(V617F)-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2(WT) cells and there was an increased glutamine metabolism in JAK2(V617F)-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in glutamine metabolism, was upregulated in the JAK2(V617F)-mutant BaF3 cells compared to the JAK2(WT) BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2(V617F)-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2(V617F)-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity.
authors.affiliation: Northport VA Medical Center, Northport, NY, USA; Department of Medicine, Stony Brook University, Stony Brook, NY, USA. Electronic address: Huichun.Zhan@va.gov.
authors.forename: Huichun
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Northport VA Medical Center, Northport, NY, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ciano
authors.affiliation: Rice University and Baylor College of Medicine, Houston, TX, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Dong
authors.affiliation: Northport VA Medical Center, Northport, NY, USA; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
mesh_terms: D045744:Cell Line, Tumor; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D009570:Nitriles; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D015854:Up-Regulation
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D005973:Glutamine; C540383:ruxolitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Cancer metabolism; Glutaminase inhibitor; Glutamine; JAK2 inhibitor; Myeloproliferative neoplasm