Upper tract urothelial carcinoma (UTUC) is a relatively rare malignancy and only accounts for 5-10% of all urothelial carcinomas. Nonetheless, management of high risk UTUC requiring radical nephrouretrectomy remains particularly challenging since only select patients have adequate renal function to tolerate cisplatin-based chemotherapy and few other proven therapeutic options exist. Cisplatin-ineligible patients with recurrent or metastatic disease who do not respond to immunotherapy have a dismal prognosis. Recent genomic studies have identified mutations in Complex of Proteins Associated with Set1(COMPASS)-like complex members in 66% of UTUC patients, but how these mutations drive UTUC carcinogenesis is virtually unknown. Our research is focused on how inactivating mutations in the COMPASS-like complex members, KMT2C, KMT2D, and KDM6A, lead to gene expression changes that support UTUC initiation and progression. In addition, we are exploring whether these mutations create a dependency on specific signaling pathways that can be exploited using novel therapies.