A new study suggests that “early seeding of subclones” may drive the “advanced stages of cancer evolution” from chronic lymphocytic leukemia (CLL) into aggressive large B-cell lymphoma.
Ferran Nadeu, PhD, of the Institut d’Investigacions Biomèdiques August Pi i Sunyer and the Centro de Investigación Biomédica en Red de Cáncer in Spain, and colleagues conducted the research because Richter’s transformation “is a paradigmatic evolution of CLL into a very aggressive large B-cell lymphoma conferring a dismal prognosis” but the mechanisms behind it “remain largely unknown.”
Dr. Nadeu and colleagues characterized the whole genome, epigenome, and transcriptome in 19 patients with CLL who were developing Richter’s transformation. They also performed single-cell DNA and RNA-sequencing analyses and functional experiments.
The researchers studied 54 longitudinal samples covering up to 19 years of disease course and “uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of [Richter’s transformation] cells already at CLL diagnosis, which were dormant for up to 19 years before transformation,” Dr. Nadeu and colleagues wrote.
A new mutational signature, which the study’s authors referred to as the single-base substitution signature, was present in the Richter’s transformation sample from seven of 18 patients.
They found new driver alterations in the cell cycle MYC, the Notch, and the NF-κB pathways. The driver alterations were “frequently targeted in single catastrophic events and by the footprints of early-in-time, treatment-related, mutational processes, including the new [single-base substitution signature] potentially associated with bendamustine and chlorambucil exposure,” Dr. Nadeu and colleagues wrote.
Dr. Nadeu and colleagues also identified a high oxidative phosphorylation, low B-cell receptor signaling transcriptional axis in Richter’s transformation, showing that inhibiting oxidative phosphorylation reduced the proliferation of Richter’s transformation cells.
“In conclusion, our comprehensive characterization of CLL evolution toward [Richter’s transformation] has revealed new genomic drivers and epigenomic reconfiguration with very early emergence of subclones driving late stages of cancer evolution, which may set the basis for developing single-cell-based predictive strategies,” Dr. Nadeu and colleagues wrote. “Furthermore, this study also identifies new [Richter’s transformation]-specific therapeutic targets and suggests that early intervention to eradicate dormant [Richter’s transformation] subclones may prevent the future development of this lethal complication of CLL.”
Nadeu F, Royo R, Massoni-Badosa R, et al. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nat Med. 2022;28(8):1662-1671