Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Homo sapiens

A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy. Overall design: HBL-1 cells (n=8) were treated with IkB kinase beta inhibitor MLN120B (25 micromolar; Calbiochem) for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3). HBL-1 cells (n=4) and OCI-Ly3 cells (n=4) were treated with MALT1 inhibitor z-VRPR-fmk (50 micromolar; Alexis Biochemicals) for 6h, 12h, 24h, and 30h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3).