Richter’s Transformation in CLL: B-Cell Receptor Signals and Genetic Lesions
Posted: Friday, June 4, 2021
According to Dimitar G. Efremov, MD, PhD, of the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, and colleagues, B-cell receptor signals seem to be directly involved in chronic lymphocytic leukemia (CLL) cell proliferation. The results of this study, which were published in the journal Blood, revealed a novel mechanism of Richter’s transformation.
The investigators conducted experiments using mice, CRISPR/Cas9 technology, cell culture and stimulation, cell proliferation assays, histology, immunohistochemistry, real-time quantitative polymerase chain reaction, immunoblotting, flow cytometry, whole-exome sequencing, and statistical analyses to examine the biologic mechanisms associated with CLL cell proliferation.
B-cell receptor engagement of human and murine CLL cells appeared to induce several positive regulators of the cell cycle; however, it also appeared to induce the negative regulators CDKN1A, CDKN2A, and CDKN2B, which block cell-cycle progression. In an in vivo murine model, the introduction of inactivating lesions in CDKN2A, CDKN2B, and in the CDKN1A regulator TP53 seemed to lead to more aggressive disease; it also appeared to result in B-cell receptor–dependent/co-stimulatory signal–independent proliferation of CLL cells in vitro.
According to the investigators, inactivating lesions in CDKN2A, CDKN2B, and TP53 commonly co-occur in cases of Richter’s syndrome; proliferation may be induced by B-cell receptor stimulation of human Richter’s syndrome cells with such lesions. Tumor cells with combined TP53 and CDKN2A/2B abnormalities seemed to be sensitive to B-cell receptor inhibition. In vitro and in vivo, these cells also appeared to be sensitive to the combination of a B-cell receptor and CDK4/6 inhibitor.
Disclosure: The study authors reported no conflicts of interest.
