Micheliolide exerts effects in MPNs by inhibiting STAT3/5 activation via covalently binding to STAT3/5 proteins

The JAK1/2 inhibitor ruxolitinib is a cornerstone of management for some subsets of BCR-ABL negative myeloproliferative neoplasms (MPNs), but some patients respond suboptimally to ruxolitinib.Here, we evaluated the efficacy of micheliolide (MCL) alone or in combination with ruxolitinib in JAK2V617F mutated MPN cell lines, MPN patient primary samples and Jak2V617F knock-in mouse model and found that MCL was able to exert effective therapeutic effects in MPNs. To gain insights of the molecular mechanisms by which MCL exerts effects, we then performed gene expression profiling analysis using data obtained from RNA-seq of UKE1 cells following treatment with MCL and/or ruxolitinib. Comparative gene expression profiling analysis of RNA-seq data for UKE1 cells which were pre-stimulated by TNF-α to mimic the pro-inflammatory micro-environment in vivo, and subsequently treated with MCL, ruxolitinib, or MCL combined with ruxolitinib, respectively.