Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

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• dc.contributor.author Nadeu, Ferran
• dc.contributor.author Massoni-Badosa, Ramon
• dc.contributor.author Ruiz Gil, Sara
• dc.contributor.author Marchese, Domenica, 1986-
• dc.contributor.author López Bigas, Núria
• dc.contributor.author Gut, Ivo Glynne
• dc.contributor.author Heyn, Holger
• dc.contributor.author Campo, Elias
• dc.date.accessioned 2022-11-07T07:30:28Z
• dc.date.available 2022-11-07T07:30:28Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship This study was supported by the la Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221, to E.C.), the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (810287, BCLLatlas, to E.C., J.I.M.-S., H.H. and I.G.), the Instituto de Salud Carlos III and the European Regional Development Fund Una Manera de Hacer Europa (PMP15/00007 to E.C. and RTI2018-094584-B-I00 to D.C.), the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE to F.N.), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245 to F.N.), the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223 to F.N.), the Generalitat de Catalunya Suport Grups de Recerca AGAUR (2017-SGR-1142 to E.C., 2017-SGR-736 to J.I.M.-S. and 2017-SGR-1009 to D.C.), the Accelerator award CRUK/AIRC/AECC joint funder partnership (AECC_AA17_SUBERO to J.I.M.-S.), the Fundació La Marató de TV3 (201924-30 to J.I.M.-S.), the Centro de Investigación Biomédica en Red Cáncer (CIBERONC; CB16/12/00225, CB16/12/00334, CB16/12/00236), the Ministerio de Ciencia e Innovación (PID2020-117185RB-I00 to X.S.P.), the Fundación Asociación Española Contra el Cáncer (FUNCAR-PRYGN211258SUÁR to X.S.P.), the Associazione Italiana per la Ricerca sul Cancro Foundation (AIRC 5 × 1,000 no. 21198 to G.G.) and the CERCA Programme/Generalitat de Catalunya. H.P.-A. is a recipient of a predoctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (FPU19/03110). A.D.-N. is supported by the Department of Education of the Basque Government (PRE_2017_1_0100). E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. This work was partially developed at the Center Esther Koplowitz (Barcelona, Spain).
• dc.format.mimetype application/pdf
• dc.identifier.citation Nadeu F, Royo R, Massoni-Badosa R, Playa-Albinyana H, Garcia-Torre B, Duran-Ferrer M et al. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nat Med. 2022 Aug;28(8):1662-71. DOI: 10.1038/s41591-022-01927-8
• dc.identifier.doi http://dx.doi.org/10.1038/s41591-022-01927-8
• dc.identifier.issn 1078-8956
• dc.identifier.uri http://hdl.handle.net/10230/54720
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Med. 2022 Aug;28(8):1662-71
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/810287
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094584-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117185RB-I00
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword B-cell lymphoma
• dc.subject.keyword Cancer epigenetics
• dc.subject.keyword Cancer genomics
• dc.subject.keyword Chronic lymphocytic leukaemia
• dc.subject.keyword Tumour heterogeneity
• dc.title Detection of early seeding of Richter transformation in chronic lymphocytic leukemia
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion