Szmyra-Polomka, M. M.; Haingartner, S.; Jantscher, S.; Bernhart, E. M.; Kovacs-Hajdu, P.; Boskova, V.; Krall, N.; Zupo, A.; Pircher, T.; Pansy, K.; Kloesch, B.; Greinix, H. T.; Beham-Schmid, C.; Vagena, F. R.; Zacharias, M.; Gaksch, L.; Prochazka, K.; Neumeister, P.; Dengler, M. A.; Deutsch, A. J.

Aggressive B-cell lymphomas are the most common lymphoid malignancies in adults, with an increasing incidence. Diffuse large B-cell lymphoma (DLBCL) is the most prevalent and highly heterogeneous type, often exhibiting poor responses to standard immuno-chemotherapy. One third of patients experience primary refractory disease or relapse, particularly those with high c-MYC and BCL-2 expression levels, which drive aggressiveness and resistance to treatment. Therefore, the development of new therapies is urgently needed. This study explores the anti-tumor properties of brusatol, both as single agent and in combination with the BCL-2 inhibitor, venetoclax, for the treatment of aggressive lymphoma cells. Brusatol inhibited lymphoma cell growth in a concentration-dependent manner in various cell lines. Further analysis revealed that brusatol is able to efficiently induce cell death in the lymphoma cells in vitro, as well as in patient-derived samples. Importantly, the effect of brusatol was strongly reduced in non-malignant lymphoid cells compared to lymphoma cells. We discovered that lymphoma cell lines highly sensitive to brusatol have elevated c-MYC expression. Brusatol treatment rapidly reduced protein expression of c-MYC and MCL-1. Protein biosynthesis analysis confirmed that brusatol induced translational inhibition in aggressive lymphoma cells. Furthermore, the combination of brusatol and venetoclax synergistically enhanced lymphoma cell death, particularly in samples with low c-MYC protein levels. Our findings suggest that brusatol has significant potential for the development of novel therapeutic strategies for aggressive lymphomas, especially for cases with high c-MYC content. Additionally, its combination with venetoclax represents a promising approach to improve treatment outcomes.