Targeting BCL2 with venetoclax is a promising therapeutic strategy for “double-proteinexpression” lymphoma with MYC and BCL2 rearrangements

Abstract

Double-hit and double-protein-expression lymphoma with MYC and BCL2 rearrangements is a rare mature B-cell neoplasm characterized by germinal center B-cell phenotype, abundant protein expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of BCL2 inhibitor venetoclax against this disease. Immunohistochemistry on the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lymphomas. In contrast, another prosurvival protein MCL1 was less expressed in this subtype, even when compared with in non-double-hit and double-protein-expression type. Furthermore, in vitro studies using two “double-hit” and double-protein-expression lymphoma-derived cell lines Karpas231 and OCI-Ly8 clearly showed that low concentration of venetoclax but not MCL1 inhibitor S63845 was sufficient to induced apoptosis in the two lines, compared with in other germinal center B-cell-derived cell lines BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and proapoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulated MCL1 protein expression probably through modulation of the protein phosphatase 2A B56α activity in Karpas231 and OCI-Ly8. Indeed, low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduction related to BCL2 and MCL1 in double-hit and double-protein-expression lymphoma cells.