Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome

J Exp Med. 2013 Oct 21;210(11):2273-88. doi: 10.1084/jem.20131448. Epub 2013 Oct 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Chromosome Deletion
  • Clone Cells
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • DNA Copy Number Variations / genetics
  • Disease Progression
  • Genetic Predisposition to Disease*
  • Genome, Human / genetics
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mutation / genetics*
  • Open Reading Frames / genetics
  • Point Mutation / genetics
  • RNA-Binding Proteins / genetics
  • Syndrome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Apoptosis Regulatory Proteins
  • CDKN2AIP protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • RNA-Binding Proteins
  • Tumor Suppressor Protein p53