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Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach de...

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Main Authors: Broséus, Julien (Author) , Hergalant, Sébastien (Author) , Vogt, Julia (Author) , Tausch, Eugen (Author) , Kreuz, Markus (Author) , Mottok, Anja (Author) , Schneider, Christof (Author) , Dartigeas, Caroline (Author) , Roos-Weil, Damien (Author) , Quinquenel, Anne (Author) , Moulin, Charline (Author) , Ott, German (Author) , Blanchet, Odile (Author) , Tomowiak, Cécile (Author) , Lazarian, Grégory (Author) , Rouyer, Pierre (Author) , Chteinberg, Emil (Author) , Bernhart, Stephan H. (Author) , Tournilhac, Olivier (Author) , Gauchotte, Guillaume (Author) , Lomazzi, Sandra (Author) , Chapiro, Elise (Author) , Nguyen-Khac, Florence (Author) , Chery, Céline (Author) , Davi, Frédéric (Author) , Hunault, Mathilde (Author) , Houlgatte, Rémi (Author) , Rosenwald, Andreas (Author) , Delmer, Alain (Author) , Meyre, David (Author) , Béné, Marie-Christine (Author) , Thieblemont, Catherine (Author) , Lichter, Peter (Author) , Ammerpohl, Ole (Author) , Guéant, Jean-Louis (Author) , Guièze, Romain (Author) , Martin-Subero, José Ignacio (Author) , Cymbalista, Florence (Author) , Feugier, Pierre (Author) , Siebert, Reiner (Author) , Stilgenbauer, Stephan (Author)
Format: Article (Journal)
Language:English
Published: 19 January 2023
In: Nature Communications
Year: 2023, Volume: 14, Pages: 1-19
ISSN:2041-1723
DOI:10.1038/s41467-022-34642-6
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-022-34642-6
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-022-34642-6
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Author Notes:Julien Broséus, Sébastien Hergalant, Julia Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos-Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan H. Bernhart, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Elise Chapiro, Florence Nguyen-Khac, Céline Chery, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie-Christine Béné, Catherine Thieblemont, Peter Lichter, Ole Ammerpohl, Jean-Louis Guéant, ICGC MMML-Seq Consortium, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, Stephan Stilgenbauer

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520 |a Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary “RS-type DLBCL” with unfavorable prognosis. 
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