Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma.

Chronic active B cell receptor(BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma(DLBCL), engages the CARD11- MALT1- BCL10(CBM) adapter complex to activate IκB kinase(IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligasescIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimeticstarget cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.