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

Abstract

The so-called “double-hit” and “double-protein-expression” lymphoma with MYC and BCL2 rearrangements is a rare, mature B-cell neoplasm characterized by a 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 the BCL2 inhibitor venetoclax in the treatment of this disease. Immunohistochemical studies of 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 pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-“double- hit” and “double-protein-expression” type. Furthermore, in vitro studies using two “double-hit” and “double-protein-expression” lymphomaderived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low concentration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce 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 on MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and the pro-apoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulates MCL1 protein expression, probably through modulation of the protein phosphatase 2A B56a activity in Karpas231 and OCI-Ly8. Indeed, a 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.