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

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, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert and Stephan Stilgenbauer ()
Additional contact information
Julien Broséus: Ulm University
Sébastien Hergalant: Université de Lorraine
Julia Vogt: Ulm University & Ulm University Medical Center
Eugen Tausch: Ulm University
Markus Kreuz: Fraunhofer Institute for Cell Therapy and Immunology IZI
Anja Mottok: Ulm University & Ulm University Medical Center
Christof Schneider: Ulm University
Caroline Dartigeas: University Hospital of Tours
Damien Roos-Weil: Hôpital de la Pitié-Salpêtrière, AP-HP
Anne Quinquenel: Hématologie Clinique
Charline Moulin: University Hospital of Nancy
German Ott: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology
Odile Blanchet: Laboratoire d’Hématologie
Cécile Tomowiak: CHU Poitiers
Grégory Lazarian: Assistance Publique-Hôpitaux de Paris
Pierre Rouyer: Université de Lorraine
Emil Chteinberg: Ulm University & Ulm University Medical Center
Stephan H. Bernhart: Leipzig University
Olivier Tournilhac: Clermont-Ferrand University Hospital
Guillaume Gauchotte: Université de Lorraine
Sandra Lomazzi: BB-0033-00035, CHRU de Nancy
Elise Chapiro: Hôpital Pitié-Salpêtrière, AP-HP
Florence Nguyen-Khac: Hôpital Pitié-Salpêtrière, AP-HP
Céline Chery: Université de Lorraine
Frédéric Davi: Université Paris Diderot
Mathilde Hunault: University Hospital of Angers
Rémi Houlgatte: Université de Lorraine
Andreas Rosenwald: University Hospital of Würzburg
Alain Delmer: Hématologie Clinique
David Meyre: Université de Lorraine
Marie-Christine Béné: University Hospital of Nantes
Catherine Thieblemont: Hôpital Saint-Louis
Peter Lichter: German Cancer Research Center (DKFZ)
Ole Ammerpohl: Ulm University & Ulm University Medical Center
Jean-Louis Guéant: Université de Lorraine
Romain Guièze: Clermont-Ferrand University Hospital
José Ignacio Martin-Subero: University of Barcelona
Florence Cymbalista: Assistance Publique-Hôpitaux de Paris
Pierre Feugier: Université de Lorraine
Reiner Siebert: Ulm University & Ulm University Medical Center
Stephan Stilgenbauer: Ulm University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-022-34642-6

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