biostudies-literatureSingh SNIAID NIH HHSNCI NIH HHSeabq2096https://www.ebi.ac.uk/biostudies/studies/S-EPMC9548378biostudies-literatureUnknown14(653)Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1⁺ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression Science translational medicineTargeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.PMC9548378P30 CA021765K08 CA255569P01 CA196539R03 CA212802R01 CA229739R01 CA247941R21 CA227926R01 AI114581R01 AI175004Young BFang JLewis PWGuo YWu QVaithiyalingam SMurphy AJAbu-Zaid AWu GRankovic ZYun MKDavidoff AMHonnell VJin HPruett-Miller SMShao YWang RHatley MXu BWang TWhite SWBowling JChen XSingh SChen EYQuarni WMaxham LChen TYang JTan HFan YEaston JGrosveld GCLi YFeng HAbdolvahabi ABajpai RPeng JfalseTargeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1⁺ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression 2022-01-01T00:00:00Z2022 Jul2026-05-28T06:11:30.552Z2025-04-05T23:32:27.868ZS-EPMC95483783585764310.1126/scitranslmed.abq2096