Targeting Metabolic Dysregulation for Ruxolitinib Failure in MPN

Background:Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis and cancer cells. MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on enhanced levels of glycolysis and oxidative phosphorylation. MPN patients often gain weight during ruxolitinib treatment effects on leptin signaling. Ruxolitinib provides symptomatic relief and can improve survival but generally fails to resolve the malignant clone,nealy 50% patients resistance to ruxolitinib.Here,we will study transcriptomic and metabolomic program in JAK2-mutant MPN who resistance to ruxolitinib.

Methods:The collection of blood samples and clinical data from MPN patients, Mice used in this study were kept in accordance with Swiss federal regulations. Multi-omics detection by transcriptome sequencing and liquid chromatography .

Results: We found that active lipid metabolism obviously in patients resistance to ruxolitinib in comparison with patients sensitive to ruxolitinib.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 key regulatory enzyme of Fatty acid metabolism gene(SREBP,FASN, ACC, SCD1) and found that pharmacological inhibition of SREBP(Betulin) reduced hematopoietic manifestations of MPNs.

Conclusion: Our findings reveal the contribution of metabolic alterations to JAK2 inhibitor failure and suggest that abnormally active lipid metabolism of mutant cells represent vulnerabilities that can be targeted for treating MPNs.

Keywords: metabolomic;resistance;resistance;Myeloproliferative