Abstract
The NFκB pathway plays a crucial role in cancer cell survival, proliferation and acquisition of resistance to therapy. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intermediary protein paracaspase important in the classical activation of NFκB. Previous studies have postulated an important role for NFκB in facilitating BCR signaling in CLL cells. Mi-2 is a novel irreversible small molecule inhibitor of MALT1. Herein, we studied the effect of MALT-1 inhibition, using Mi-2, on the survival of CLL cells. Mi-2 rapidly reduced CLL cell viability in a dose-dependent manner. This effect was associated with the intrinsic apoptotic pathway activation, a robust increase in cleaved PARP and accompanied by a prominent decrease in Mcl-1 and BCL2 levels. The pro-apoptotic effect of Mi-2 was observed in CLL cells of both low and high-risk prognostic features. Accordingly pre-treatment with Mi-2 resulted in inhibition of IκB phosphorylation after BCR activation or even reduction below its basal level. Taken together, our results provide proof of the concept that MALT1 inhibition by the small molecule Mi-2 can efficiently induce apoptosis in CLL cells. In light of the importance of the BCR and NFκB pathways in the pathogenesis of CLL, MALT1 is a potential therapeutic target in this disease. This is particularly important in the era of novel agents used to treat CLL, when resistance to these drugs emerges over time. Keywords: B-cell receptor (BCR); chronic lymphocytic leukemia (CLL); MALT1.
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