A new study defines “distinct molecular subtypes” of Richter syndrome, according to its authors.
Erin M. Parry, MD, PhD; Ignaty Leshchiner PhD; and Romain Guièze, MD; of the Broad Institute of the Massachusetts Institute of Technology and Harvard and colleagues conducted the research to “decipher the genetics underlying this transformation” from chronic lymphocytic leukemia (CLL).
They computationally deconvoluted admixtures of CLL cells and Richter syndrome cells from 52 patients with Richter syndrome and evaluated paired CLL-Richter syndrome whole-exome sequencing data.
The researchers discovered Richter syndrome-specific somatic driver mutations in genes including IRF2BP2, SRSF1, B2M, DNMT3A, and CCND3. They also found recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which they confirmed in 45 independent Richter syndrome cases and in an external set of Richter syndrome whole genomes.
Clonally related Richter syndrome was “largely distinct from diffuse large B cell lymphoma” through unsupervised clustering, according to the study’s authors. The researchers also “distinguished pathways that were dysregulated” in Richter syndrome versus CLL and “detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states,” they wrote.
Overall, the study defined “distinct molecular subtypes” of Richter syndrome and “highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring,” the study’s authors concluded.
Parry EM, Leshchiner I, Guièze R, et al. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome. Nat Med. 2023;29(1):158-169.