Understanding the ‘Black Box’ of Genetic Evolution From CLL to Richter’s Syndrome

By: Lauren Velentzas
Posted: Tuesday, March 21, 2023

For up to 1% of patients who have chronic lymphocytic leukemia (CLL), their disease will develop into the more aggressive Richter’s syndrome (RS). Catherine J. Wu, MD, of Dana-Farber Cancer Institute, Boston, and colleagues used matched samples of CLL and RS cells to evaluate paired CLL-RS whole-exome sequencing data and trace the transformative changes. The findings, originally presented at the 2022 American Society of Hematology Annual Meeting and Exposition, were recently published in Nature Medicine.

“The treatments for CLL and [RS] are very different, so it’s critical that doctors be able to determine, as early as possible, when CLL has ‘crossed over’ to become Richter’s,” said Dr. Wu in a Dana-Farber press release. “Our findings in this study hold the promise of an earlier, more definitive diagnosis based on the molecular makeup of the tumor cells.”

Data were gathered from tissue samples of a cohort of 52 patients with RS. Samples taken before the patients’ diagnoses with RS were paired with those taken after diagnosis to identify genetic changes, and the RS-specific somatic driver mutations discovered included IRF2BP2, SRSF1, B2M, DNMT3A, and CCND3, which were distinct from circulating CLL. Pathways were distinguished that identified intermediate cell states and were dysregulated in RS versus CLL.

The study also sequenced DNA in plasma samples from 24 patients and found that “genomic features of Richter’s were indeed detectable in the plasma.” In a substantial portion of patients, RS cells did not share a genetic history with their CLL cells. These RS cells arose independently, with no connection to the earlier disease and were largely distinct from diffuse large B-cell lymphoma. The study authors concluded there are distinct molecular subtypes of RS and cell-free DNA analysis may be a potential tool for early diagnosis and patient monitoring.

Disclosure: For the full list of study authors’ disclosures, visit nature.com.

Nature Medicine