Nadeu, FerranMassoni-Badosa, RamonRuiz Gil, SaraMarchese, Domenica, 1986-López Bigas, NúriaGut, Ivo GlynneHeyn, HolgerCampo, Elias2022-11-072022-11-072022Nadeu 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/s41591-022-01927-81078-8956http://hdl.handle.net/10230/54720Richter 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41591-022-01927-8B-cell lymphomaCancer epigeneticsCancer genomicsChronic lymphocytic leukaemiaTumour heterogeneityinfo:eu-repo/semantics/openAccess