cIAP1/2 Promote NFκB Activation and Survival in ABC DLBCL

The activated B cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive B-cell receptor (BCR)–mediated activation of nuclear factor κ B (NFκB) signaling. NFκB pathway proteins, such as the IKK kinase and its regulatory subunit NEMO, are largely regulated by K63-linked and linear polyubiquitination driven by the linear ubiquitin chain assembly complex (LUBAC) protein, which is associated with the CARD11–BCL10–MALT1 (CBM) complex; however, it remains unclear how CBM recruits and regulates LUBAC activity. The cellular inhibitors of apoptosis proteins (cIAP1 and cIAP2) are E3 ubiquitin ligases that have been implicated in regulation of NFκB signaling in addition to their known roles in inhibiting apoptosis. Attempts to inhibit cIAP and induce apoptosis in cancer cells are under way with SMAC mimetics in development. Yang and colleagues showed that the BIRC2 and BIRC3 genes, which encode for the cIAP1 and cIAP2 E3 ubiquitin ligase proteins, were recurrently amplified in ABC DLBCL tumors, and that chemical or genetic suppression of cIAP1/2 inhibited NFκB pathway activity and was toxic in BCR-dependent, but not BCR-independent, ABC DLBCL cell lines in vitro and in vivo. Mechanistically, cIAP1/2 were shown to regulate the NFκB pathway by binding MALT1 and regulating K63-linked ubiquitination of BCL10, which promoted its association with NEMO and IKK recruitment to the CBM complex. Autoubiquitination of cIAP1/2 mediated binding and recruitment of the LUBAC subunit SHARPIN to the CBM complex and was required for NEMO and BCL10 ubiquitination in BCR-dependent ABC DLBCL cells. Together, these data highlight cIAP1/2 E3 ligases as critical components of the CBM complex that regulate NF-κB pathway activation and are required for survival in BCR-dependent ABC DLBCL cells. Furthermore, these findings support evaluation of cIAP1/2 antagonists such as SMAC mimetics that are already in clinical development in ABC DLBCL.

Yang Y, Kelly P, Shaffer AL 3rd, Schmitz R, Yoo HM, Liu X, et al. Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B cell lymphoma. Cancer Cell 2016;29:494–507.