Integrated transcriptomic and metabolomic analyses provide mechanistic insights into the pro-proliferative role of DARS in human MPN cell models

Previous studies have shown that DARS is highly expressed in patients with myeloproliferative neoplasms (MPN), and these patients have higher disease burdens. However, the mechanism by which DARS promotes the proliferation of MPN cells remains unclear. Here, we explored the tumor-intrinsic role of DARS in human MPN cell models and the associated molecular mechanisms using an integrated multi-omics approach. DARS depletion suppressed the proliferation of MPN cells in vitro and xenograft tumor growth in vivo, induced cell-cycle arrest, and promoted apoptosis. Metabolomic analysis identified 190 differential metabolites associated with DARS depletion in MPN cells, many of which were enriched in cancer-related pathways. Transcriptomic analysis showed that DARS depletion was associated with altered expression of more than 2,000 genes; integrated analysis of transcriptomic and metabolomic data indicated potential involvement of calcium signaling, pyrimidine metabolism, and nucleotide metabolism. Re-analysis of independent public MPN datasets further supported the association of DARS with disease context and immune-infiltration features. Overall, our results support a pro-proliferative role of DARS in human MPN cell models. DARS depletion was associated with PI3K/AKT-related transcriptional and metabolic alterations, and reactivation of PI3K/AKT partially rescued the phenotypic changes induced by DARS depletion.