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Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. 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