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Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA\u2010 and protein\u2010based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual\u2010color break\u2010apart fluorescence <jats:italic>in situ<\/jats:italic> hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD<jats:sup>+<\/jats:sup>\/NADH ratio, and supplementation with \u03b2\u2010nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. \u00a9 2024 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6340","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T07:19:47Z","timestamp":1722583187000},"page":"228-240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>NMRK2<\/scp> is an efficient diagnostic indicator for Xp11.2 translocation renal cell carcinoma"],"prefix":"10.1002","volume":"264","author":[{"given":"Huayi","family":"Feng","sequence":"first","affiliation":[{"name":"Chinese PLA Medical School  Beijing PR China"},{"name":"Department of Urology, The Third Medical Center Chinese PLA General Hospital  Beijing PR 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