Abstract
CIC-rearranged sarcoma (CRS) is a rare and aggressive malignancy driven by CIC fusion proteins, primarily CIC-DUX4, with a propensity for brain metastases. Other fusion partners, such as CIC-NUTM1, have been identified in a subset of pediatric primitive neuroectodermal tumors. Native CIC functions as a transcriptional repressor of genes downstream of the RTK/Ras/ERK pathway, including ETV1/4/5, which play a key role in CRS oncogenesis. Interestingly, CIC fusions convert a transcriptional repressor into an activator, though the precise oncogenic mechanisms remain unclear. Our data reveal that CIC fusions activate the JAK1/STAT1/3 pathway, leading to increased mRNA and protein expression of ETV1/4/5. Patient-derived CRS cell lines (NCC-SCC-89/C) exhibit high JAK1/STAT1/3 activation compared to fusion-negative sarcoma lines. JAK1 inhibition with Solcitinib or Ruxolitinib suppresses STAT1/3 phosphorylation, ETV1/4/5 expression, cell proliferation, and tumorigenicity. DUX4’s role in histone acetylation and STAT1’s interaction with the p300/CBP complex suggest a transcriptional activation mechanism. We demonstrate that CIC fusions enhance STAT1/3 binding to ETV1/4/5 promoters, while JAK1 inhibition reduces histone acetylation and suppresses transcription. In vivo, Ruxolitinib significantly reduced tumor volume, STAT1/3 activation, and ETV1/4/5 expression in CRS xenografts. Additionally, Ruxolitinib combined with doxorubicin exhibited synergistic effects, further reducing tumor volume. In conclusion, we identify JAK1/STAT1/3 as a key oncogenic driver in CRS, promoting histone acetylation and ETV1/4/5 upregulation, leading to increased cellular proliferation. These findings support JAK1/STAT1/3 inhibition as a promising therapeutic strategy for CRS and warrant further preclinical investigation.