Nadeu Prat, FerranRoyo, RominaMassoni Badosa, RamonPlayà Albinyana, HeribertGarcia-Torre, BeatrizDuran Ferrer, MartíDawson, Kevin J.Kulis, MartaDíaz Navarro, AnderVillamor i Casas, NeusMelero, Juan L.Chapaprieta, VicenteDueso Barroso, AnaDelgado, JulioMoia, RiccardoRuiz Gil, SaraMarchese, DomenicaGiró, AriadnaVerdaguer Dot, NúriaClot Razquin, GuillemRozman, MaríaFrigola, GerardRivas Delgado, AlfredoBaumann, TychoAlcoceba, MiguelGonzález,MarcoCliment, FinaAbrisqueta Costa, PauCastellví, JosepBosch, FrancescAymerich Gregorio, MartaEnjuanes, AnnaRuiz Gaspà, SilviaLópez Guillermo, ArmandoJares Gerboles, PedroBeà Bobet, Sílvia M.Capella Gutiérrez, Salvador Jesús, 1985-Gelpí Buchaca, Josep LluísLópez Bigas, NúriaTorrents Arenales, DavidCampbell, Peter J.Gut, Ivo G.Rossi, DavideGaidano, GianlucaPuente, Xose S.Garcia Roves, Pablo M.Colomer Pujol, DolorsHeyn, HolgerMaura, FrancescoMartín-Subero, José IgnacioCampo Güerri, Elias2024-09-042024-09-042022-08-111078-8956https://hdl.handle.net/2445/214988Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.37 p.application/pdfengcc-by(c) Nadeu, Ferran et al., 2022http://creativecommons.org/licenses/by/4.0/Leucèmia limfocítica crònicaLimfomesGenèticaPatologiaChronic lymphocytic leukemiaLymphomasGeneticsPathologyinfo:eu-repo/semantics/article7244312024-09-04info:eu-repo/semantics/openAccess35953718