Early Clones Expand in Richter Transformation of Chronic Lymphocytic Leukemia

The evolution of chronic lymphocytic leukemia (CLL) into an aggressive B-cell lymphoma, known as Richter transformation (RT), often follows chemoimmunotherapy or targeted therapy. RT has a poor clinical prognosis, and the mechanisms that underlie RT development are not well understood. To investigate the evolutionary history of RT, Nadeu, Royo, Massoni-Badosa, Playa-Albinyana, Garcia-Torre, and colleagues profiled longitudinal tumor samples from patients in whom CLL transformed into diffuse large B-cell lymphoma (n = 17), plasmablastic lymphoma (n = 1), or prolymphocytic leukemia (n = 1). Whole-genome sequencing and epigenomic analyses revealed the mutational landscape of RT, which indicated increased (epi)genomic complexity from CLL diagnosis to RT and highlighted new candidate RT drivers, including cell-cycle regulators, chromatin remodelers, and MYC and NF-κB pathway members. Mutational pattern analysis uncovered 11 distinct signatures, including a novel RT-specific single-base substitution signature in samples previously treated with alkylating agents. Notably, the major clone at the time of transformation could be detected in samples well before clinical manifestation of RT and often after treatment, with evidence supporting a single-cell expansion model in which mutational diversity occurs early in CLL progression, followed by emergence of RT from a preexisting subclone that expands due to selection pressure. Single-cell analyses confirmed that subclones with genomic and transcriptomic features of RT were seeded as early as 19 years before final RT expansion. In contrast to CLL, RT samples downregulated B-cell receptor (BCR) signaling while increasing chromatin activation and accessibility in regions enriched for the transcription factor TEAD4, which regulates genes involved in oxidative phosphorylation (OXPHOS). This OXPHOS^hi–BCR^lo transcriptional axis was also observed in dormant RT subclones at early stages before transformation, and in vitro studies demonstrated that pharmacologic OXPHOS inhibition slowed proliferation of OXPHOS^hi RT cells. In summary, this study examines the evolutionary history of RT and proposes an avenue of therapeutic intervention to target early-emerging subclones.

Nadeu F, Royo R, Massoni-Badosa R, Playa-Albinyana H, Garcia-Torre B, Duran-Ferrer M, et al. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nat Med 2022 Aug 11 [Epub ahead of print].

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