期刊
NATURE MEDICINE
卷 28, 期 8, 页码 1662-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01927-8
关键词
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资金
- la Caixa Foundation [LCF/PR/HR17/52150017, HR17-00221]
- European Research Council under the European Union's Horizon 2020 Research and Innovation Program [810287]
- Instituto de Salud Carlos III
- European Regional Development Fund Una Manera de Hacer Europa [PMP15/00007, RTI2018-094584-B-I00]
- American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research) [21-40-11-NADE]
- European Hematology Association (EHA Junior Research Grant 2021) [RG-202012-00245]
- Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022) [LADY_TATA_21_3223]
- Generalitat de Catalunya Suport Grups de Recerca AGAUR [2017-SGR-1142, 2017-SGR-736, 2017-SGR-1009]
- Accelerator award CRUK/AIRC/AECC joint funder partnership [AECC_AA17_SUBERO]
- Fundacio La Marato de TV3 [201924-30]
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC) [CB16/12/00225, CB16/12/00334, CB16/12/00236]
- Ministerio de Ciencia e Innovacion [PID2020-117185RB-I00]
- Fundacion Asociacion Espanola Contra el Cancer [FUNCAR-PRYGN211258SUaR]
- Associazione Italiana per la Ricerca sul Cancro Foundation (AIRC) [21198]
- CERCA Programme/Generalitat de Catalunya
- Spanish Ministry of Science, Innovation and Universities [FPU19/03110]
- Department of Education of the Basque Government [PRE_2017_1_0100]
By analyzing the genome, epigenome, and transcriptome of CLL cases developing RT, this study reveals the presence of minute subclones with RT features at CLL diagnosis and identifies potential therapeutic targets through OXPHOS inhibition.
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. Single-cell genomic and transcriptomic analyses of longitudinal samples of patients with Richter syndrome reveal the presence and dynamics of clones driving transformation from chronic lymphocytic leukemia years before clinical manifestation
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