Latest findings open the way for the development of personalised combination treatments for patients with Richter transformation.
A study recently published in the journal Blood by the Molecular Hematology Group in Trieste, led by Dr. Dimitar Efremov, has identified the mechanism through which combined genetic lesions in the tumor suppressor TP53 and the cell cycle inhibitors CDKN2A and CDKN2B trigger the transformation of chronic lymphocytic leukemia into highly aggressive diffuse large B cell lymphoma, a syndrome known as Richter transformation. The study presents an in vivo model useful to test novel therapies for patients with Richter syndrome.
Richter transformation is a serious complication that occurs in up to 10% of patients with chronic lymphocytic leukemia and represents an important unmet clinical need for which no effective therapy exists. To generate an in vivo model appropriate for testing of novel therapies, the ICGEB researchers used CRISPR/Cas9 genome editing to simultaneously introduce into murine leukemic cells several genetic lesions that are recurrently detected in the tumors of patients with Richter transformation. These included inactivating genetic lesions in the tumor suppressor TP53 and the cell cycle inhibitors CDKN2A and CDKN2B, which co-occur in more than one third of cases with Richter transformation. Tumor cells with such genetic lesions displayed morphological features of Richter transformation in vivo and had acquired the capacity to proliferate spontaneously in vitro. These findings suggest that combined deficiency of TP53, CDKN2A and CDKN2B transforms the leukemic cells by making them less dependent on growth-promoting signals from the tumour microenvironment. Importantly, subsequent in vitro and in vivo experiments with these cells showed that they are particularly sensitive to combinations of drugs that inhibit kinases involved in B cell receptor signaling and regulation of the G1 phase of the cell cycle, thus providing the rationale for testing combinations of these drugs in the clinic.
“The recent development of several highly effective novel targeted therapies, such as BCR and BCL2 inhibitors, has significantly improved the outcome of patients with chronic lymphocytic leukemia, but no progress has been made with respect to the management of patients with Richter transformation, who continue to have a very poor prognosis. The models that we developed in this study allow the testing of novel personalised combination treatments for this condition and have already resulted in the identification of a promising drug combination that requires further validation in the clinic,” comments Dr. Efremov.
The study was supported by grants from “Fondazione AIRC per la ricerca sul cancro” and the Italian Ministry of Health. The CRISPR/Cas9 editing approach that was developed in this study is currently being employed by the Molecular Hematology Group to generate additional murine leukemias with patient-specific genetic defects, which will provide an important preclinical tool for in vivo testing of other drug combinations for personalized treatment of chronic lymphocytic leukemia and Richter transformation.
Chakraborty, S., … Efremov, D.G. B Cell Receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter Transformation. Blood (2021) https://doi.org/10.1182/blood.2020008276