Richter syndrome: novel insights into the biology of transformation

Abstract

Although the genetic landscape of chronic lymphocytic leukemia (CLL) has been broadly profiled by large-scale sequencing studies performed over the past decade, the molecular basis of the transformation of CLL into aggressive lymphoma, or Richter syndrome (RS), has remained incompletely characterized. Recent advances in computational methods of clonal deconvolution, as well as extensive sample collection efforts in this rapidly progressive malignancy, have now enabled comprehensive analysis of paired CLL and RS samples and have led to multiple new studies investigating the genetic, transcriptomic, and epigenetic origins of RS. In parallel, new genetically engineered and xenograft mouse models have provided the opportunity for gleaning fresh biological and mechanistic insights into RS development and stepwise evolution from antecedent CLL. Altogether, these studies have defined RS driver lesions and CLL risk lesions and identified pathways dysregulated in transformation. Moreover, unique molecular subtypes of RS have been revealed, including a disease marked by profound genomic instability with chromothripsis/chromoplexy and whole genome duplication. Novel profiling approaches, including single-cell DNA and transcriptome sequencing of RS biopsy specimens and cell-free DNA profiling of patient plasma, demonstrate promise for the timely identification of RS clones and may translate to noninvasive identification and early diagnosis of RS. This review summarizes the recent scientific advances in RS and supports the integrated study of human genomics with mouse modeling to provide an advanced understanding of the biological underpinnings of transformation. These recent studies have major implications for much-needed novel therapeutic strategies for this still largely incurable malignancy.

Graphical abstract

Figure 1.

New understanding of RS. Insights into the biology of RS gained by recent large-scale studies profiling the genetic, transcriptomic, and epigenetic features of RS, and by the generation of mouse GEMM and PDX models highly reflective of human RS. GEMM, genetically engineered mouse model; PDX, patient-derived xenograft.

Figure 2.

Genetic lesions and affected cellular pathways of RS. (A) Recurrent driver lesions and impacted B-cell pathways in RS. Image partially created with BioRender software. (B) Timing of major RS pathway alterations in the evolution of CLL toward RS. CNG, copy number gain; CNL, copy number loss; GOF, gain of function mutations; LOF, loss of function mutations.

Figure 3.

Investigational therapeutic landscape of RS. Small molecule targeted agents and immune therapeutics currently in open or recently completed clinical trials for RS. Image created with BioRender software.

Figure 4.

Translational potential of RS investigation. (A) Examination of single cells and/or plasma offers opportunity for early detection of RS clones or RS molecular changes, which may translate to enable early or noninvasive diagnosis. (B) The potential of molecular characterization along with traditional histopathology assessment to refine RS diagnosis.