Inhibition of MALT1 protease activity is selectively toxic for activated B cell–like diffuse large B cell lymphoma cells

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell–like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11–BCL10–MALT1 (CBM) complexes couple upstream events to IκB kinase (IKK)/NF-κB activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here, we demonstrate preassembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL, but not in germinal center B cell–like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity, and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.

The Paracaspase MALT1

“…independently went on to investigate whether the dependence extended to the proteolytic activity of MALT1 [80, 81]. They used a fluoromethylketone tetrapeptide inhibitor (Z-VRPR-FMK) that was loosely based on the sequence of the discovered substrates to investigate the effect of MALT1 inhibition on different B cell lymphoma cell lines.…”

“…The inhibition of MALT1 proteolytic activity led to decreased cell viability in cell lines derived from ABC-DLBCL. Cell lines derived from other types of B cell lymphomas like GCB-DLBCL, Burkitt’s lymphoma, and marginal zone lymphoma were not affected [80, 81]. These results suggested that it is not only the scaffolding function of MALT1 that is important for its function but also its proteolytic activity.…”

The CBM signalosome: Potential therapeutic target for aggressive lymphoma?

“…Although it has similar caspase fold as other caspases, it cleaves after arginine residue and distinguishes itself from conventional caspases [17]. MALT1 cleavage activity is linked to the pathogenesis of ABC-DLBCL, the most chemotherapy-resistant and clinically challenging form of DLBCL [58,59]. Targeting MALT1 proteolytic activity for ABC-DLBCL has become a hot research topic recently [60,61].…”

A New “Brew” of MALT1 Inhibitors

“…MALT1 cleaves and disables A20 (TNFAIP3) and CYLD, both negative regulators of NF-κB, thereby potentiating NF-κB signaling. Based on these results in normal lymphocytes, two groups demonstrated that MALT protease activity is required for NF-κB activity and survival of ABC DLBCL cells (Ferch et al, 2009; Hailfinger et al, 2009). A peptide inhibitor of MALT1 paracaspase activity was toxic to ABC DLBCL cell lines, but not to models of other lymphoma subtypes.…”