Fischer, UteForster, MichaelRinaldi, AnnaRisch, ThomasSungalee, StephanieWarnatz, Hans-JoergBornhauser, BeatGombert, MichaelKratsch, ChristinaStuetz, Adrian M.Sultan, MarcTchinda, JoelleWorth, Catherine L.Amstislavskiy, VyacheslavBadarinarayan, NandiniBaruchel, AndreBartram, ThiesBasso, GiuseppeCanpolat, CengizCario, GunnarCave, HeleneDakaj, DardaneDelorenzi, MauroDobay, Maria PamelaEckert, CorneliaEllinghaus, EvaEugster, SabrinaFrismantas, ViktorasGinzel, SebastianHaas, Oskar A.Heidenreich, OlafHemmrich-Stanisak, GeorgHezaveh, KebriaHoell, Jessica I.Hornhardt, SabineHusemann, PeterKachroo, PriyadarshiniKratz, Christian P.te Kronnie, GeertruyMarovca, BlerimNiggli, FelixMcHardy, Alice C.Moorman, Anthony V.Panzer-Gruemayer, RenatePetersen, Britt S.Raeder, BenjaminRalser, MeryemRosenstiel, PhilipSchaefer, DanielSchrappe, MartinSchreiber, StefanSchuette, MoritzStade, BjoernThiele, Ralfvon der Weid, NicolasVora, AjayZaliova, MarketaZhang, LanghuiZichner, ThomasZimmermann, MartinLehrach, HansBorkhardt, ArndtBourquin, Jean-PierreFranke, AndreKorbel, Jan O.Stanulla, MartinYaspo, Marie-Laure2023-02-212023-02-212015-01-0110.1038/ng.3362https://hdl.handle.net/11443/2808http://dx.doi.org/10.1038/ng.3362TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.ArticleWOS:000360394100012