Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome

Giulia Fabbri, Hossein Khiabanian, Antony B. Holmes, Jiguang Wang, Monica Messina, Charles G. Mullighan, Laura Pasqualucci, Raul Rabadan, Riccardo Dalla-Favera

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

Original languageEnglish (US)
Pages (from-to)2273-2288
Number of pages16
JournalJournal of Experimental Medicine
Issue number11
StatePublished - Oct 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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