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

Julien BroseusSebastien HergalantJulia VogtEugen TauschMarkus KreuzAnja MottokChristof SchneiderCaroline DartigeasDamien Roos-WeilAnne QuinquenelCharline MoulinGerman OttOdile BlanchetCécile TomowiakGrégory LazarianPierre RouyerEmil ChteinbergStephan H BernhartOlivier TournilhacGuillaume GauchotteSandra LomazziElise ChapiroFlorence Nguyen-KhacCéline CheryFrédéric DaviMathilde HunaultRémi HoulgatteAndreas RosenwaldAlain Jacques DelmerDavid MeyreMarie Christine BeneCatherine ThieblemontPeter LichterOle AmmerpohlJean-Louis Guéantnull nullRomain GuièzeJosé Ignacio Martin-SuberoFlorence CymbalistaPierre FeugierReiner SiebertStephan Stilgenbauer
Published in: Nature communications (2023)
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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