Enhanced survival of BEN'I'A patient B cells is dependent on MALT1 protease activity

Abstract BENTA (B cell Expansion with NF-κB and T cell Anergy) disease is a rare, selective B cell lymphoproliferative disorder caused by gain-of-function (GOF) mutations in the lymphocyte scaffolding molecule CARD11. CARD11 is required for downstream activation of NF-κB following antigen receptor engagement, which normally triggers recruitment of BCL10 and MALT1. MALT1 serves both scaffolding and proteolytic functions that initiate and amplify canonical NF-κB signaling. It still remains unclear how continuous CARD11 signaling ultimately drives massive B cell accumulation in BENTA patients. Here we show that in contrast to normal human B cells, BENTA patient B cells exhibited a striking resistance to apoptosis in cell culture, particularly after stimulation. Enhanced survival of patient cells was dependent on MALT1 protease, which is activated constitutively by CARD11 GOF mutants. Treatment with a novel, specific low molecular weight inhibitor of MALT1 protease completely restored apoptosis sensitivity in BENTA patient B cells. RNA-Seq analyses revealed that MALT1 protease inhibition induced a specific subset of pro-apoptotic genes in activated patient B cells, and downregulated multiple genes associated with cell cycle progression and metabolism, in addition to several NF-κB target genes. Although not strictly required for CARD11-dependent NF-κB activation, our results imply that MALT1 protease function governs a pro-survival signaling program in BENTA B cells that likely contributes to the profound B cell lymphocytosis that distinguishes this disease. MALT1 protease thus represents an attractive therapeutic target for reducing B cell burden in these patients, thereby lowering the risk of B cell malignancy later in life.