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.

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Upregulates glutamine metabolism enzymes and transporters 6,31,48,145,177 KRAS mutations Drives dependence on glutamine metabolism, suppresses GLUD, and drives NADPH via malic enzyme 1 (ME1) 34,108,119,157,158 HIF1α or HIF2α stabilization Drives reductive carboxylation of glutamine to citrate for lipid production [89][90][91] HER2 upregulation Activates glutamine metabolism through MYC and NF-κB 156,220 p53, p63, or p73 activity Activates GLS2 expression 55,56,62,63 JAK2-V617F mutation Activates GLS and increases glutamine metabolism 221 mTOR upregulation Promotes glutamine metabolism via induction of MYC 155 and GLUD 69,73 or aminotransferases 117 NRF2 activation Promotes production of glutathione from glutamine 222 TGFβ-WNT upregulation Promotes SNAIL and DLX2 activation, which upregulate GLS and activates epithelial-mesenchymal transition 183 PKC zeta loss Stimulates glutamine metabolism through serine synthesis 223 …”

The elevated glutaminolysis of bladder cancer and T cells in a simulated tumor microenvironment contributes to the up-regulation of PD-L1 expression by interferon-γ

“… 39 Other studies also confirm that glutamine metabolism is a potential target for cancer therapy. 40 , 41 These studies prove that glutamine metabolism is essential for cancer survival and progression. In this study, glutaminolysis was also enhanced in bladder cancer cells co-cultured with T cells ( Figure 6B and D ).…”

Apatinib induces 3‐hydroxybutyric acid production in the liver of mice by peroxisome proliferator‐activated receptor α activation to aid its antitumor effect

“…Recent evidence suggests that cancer is a type of metabolic disease . Recent metabolomics studies in oncology found that various types of cancer or different stages of cancer development show different metabolic phenotypes such as aerobic glycolysis (the Warburg effect), one‐carbon metabolism and glutaminolysis . Several biomarkers have been identified in earlier diagnosis, distinguishing various stages of tumor occurrence and progression, as well as biomarkers for treatment response of anticancer drugs.…”