Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Richter 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 si...

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Authors: Nadeu Prat, Ferran, Royo, Romina, Massoni Badosa, Ramon, Playà Albinyana, Heribert, Garcia-Torre, Beatriz, Duran Ferrer, Martí, Dawson, Kevin J., Kulis, Marta, Díaz Navarro, Ander, Villamor i Casas, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz Gil, Sara, Marchese, Domenica, Giró, Ariadna, Verdaguer Dot, Núria, Clot Razquin, Guillem, Rozman, María, Frigola, Gerard, Rivas Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, González,Marco, Climent, Fina, Abrisqueta Costa, Pau, Castellví, Josep, Bosch, Francesc, Aymerich Gregorio, Marta, Enjuanes, Anna, Ruiz Gaspà, Silvia, López Guillermo, Armando, Jares Gerboles, Pedro, Beà Bobet, Sílvia M., Capella Gutiérrez, Salvador Jesús, 1985-, Gelpí Buchaca, Josep Lluís, López Bigas, Núria, Torrents Arenales, David, Campbell, Peter J., Gut, Ivo G., Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., Garcia Roves, Pablo M., Colomer Pujol, Dolors, Heyn, Holger, Maura, Francesco, Martín-Subero, José Ignacio, Campo Güerri, Elias
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/214988
Online Access:https://hdl.handle.net/2445/214988
Access Level:Open access
Keyword:Leucèmia limfocítica crònica
Limfomes
Genètica
Patologia
Chronic lymphocytic leukemia
Lymphomas
Genetics
Pathology
Description
Summary:Richter 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.

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