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Targeting glutamine metabolism in myeloproliferative neoplasms
Huichun Zhan1, Kristen Ciano2, Katherine Dong3
1Northport VA Medical Center, Northport, NY, USA; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
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.
Insights
The JAK2(V617F) mutation in myeloproliferative neoplasms (MPNs) increases glutamine metabolism. Inhibiting glutaminase (GLS) enhances Ruxolitinib
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Myeloproliferative neoplasms (MPNs) are often driven by the JAK2(V617F) mutation.
- Ruxolitinib, a JAK2 inhibitor, is an FDA-approved MPN treatment but has dose-limiting toxicities.
- Understanding the metabolic alterations in MPNs is crucial for developing more effective therapies.
Purpose of the Study:
- To investigate the metabolic state and glutamine metabolism in JAK2(V617F)-mutant cells compared to wild-type.
- To assess the role of glutaminase (GLS) in MPN pathogenesis and its potential as a therapeutic target.
- To evaluate the combined effect of GLS inhibition and Ruxolitinib in MPN models.
Main Methods:
- Metabolic analysis (oxygen consumption, extracellular acidification) of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells.
- Quantification of glutamine metabolism and glutaminase (GLS) expression in cell lines and patient-derived CD34+ cells.
- Assessment of the synergistic effect of GLS inhibitors and Ruxolitinib on cell growth.
Main Results:
- JAK2(V617F)-mutant cells exhibit increased oxygen consumption and extracellular acidification rates.
- Glutamine metabolism and GLS expression are significantly upregulated in JAK2(V617F)-mutant cells and MPN patient progenitor cells.
- GLS inhibition potentiates the anti-proliferative effects of Ruxolitinib in both cell lines and patient cells.
Conclusions:
- Upregulated glutamine metabolism, mediated by GLS, is a key metabolic feature of JAK2(V617F)-driven MPNs.
- Targeting GLS in combination with JAK2 inhibitors like Ruxolitinib may offer a more effective therapeutic strategy.
- Combined therapy could allow for lower Ruxolitinib doses, potentially mitigating treatment-related toxicities.
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