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It accounts for 15% of childhood and 25% of adult ALL cases. GNE-987 is a novel chimeric molecule developed using proteolysis-targeting chimeras (PROTAC) technology for targeted therapy. It consists of a potent inhibitor of the bromodomain and extraterminal (BET) protein, as well as the E3 ubiquitin ligase Von Hippel-Lindau (VHL), which enables the effective induction of proteasomal degradation of BRD4. Although GNE-987 has shown persistent inhibition of cell proliferation and apoptosis, its specific antitumor activity in T-ALL remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antitumor effect of GNE-987 in T-ALL. To achieve this, we employed technologies including RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and CUT&amp;Tag. The degradation of BET proteins, specifically BRD4, by GNE-987 has a profound impact on T-ALL cell. In in vivo experiments, sh-BRD4 lentivirus reduced T-ALL cell proliferation and invasion, extending the survival time of mice. The RNA-seq and CUT&amp;Tag analyses provided further insights into the mechanism of action of GNE-987 in T-ALL. These analyses revealed that GNE-987 possesses the ability to suppress the expression of various genes associated with super-enhancers (SEs), including lymphoblastic leukemia 1 (LCK). By targeting these SE-associated genes, GNE-987 effectively inhibits the progression of T-ALL. Importantly, SE-related oncogenes like LCK were identified as critical targets of GNE-987. Based on these findings, GNE-987 holds promise as a potential novel candidate drug for the treatment of T-ALL.<\/jats:p>","DOI":"10.1093\/carcin\/bgae006","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T01:02:38Z","timestamp":1706835758000},"page":"424-435","source":"Crossref","is-referenced-by-count":13,"title":["The BET inhibitor GNE-987 effectively induces anti-cancer effects in T-cell acute lymphoblastic leukemia by targeting enhancer regulated genes"],"prefix":"10.1093","volume":"45","author":[{"given":"Juanjuan","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Sixth Affiliated Hospital of Nantong University , Yancheng 224000 , China"},{"name":"Department of Pediatrics, Yancheng Third People\u2019s Hospital , Yancheng 224000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Tao","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University , Columbus, OH 43210 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyan","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yancheng Third People\u2019s Hospital , Yancheng 224000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongting","family":"Ji","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiandan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolu","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University , Suzhou 215003 , 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