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

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Yibin Yang, Priscilla Kelly, Arthur L. Shaffer, Roland Schmitz, Hee Min Yoo, Xinyue Liu, Da Wei Huang, Daniel Webster, Ryan M. Young, Masao Nakagawa, Michele Ceribelli, George W. Wright, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Wing C. Chan, Elaine S. Jaffe, Randy D. Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M. Staudt
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 ligases cIAP1 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 mimetics target 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.

Teaser

Yang et al. show that cIAP1 and cIAP2 mediate K63 ubiquitination of BCL10, thus are essential for B cell receptor (BCR)-dependent NF-κB activity in the ABC subtype of diffuse large B cell lymphoma (DLBCL). SMAC mimetics target cIAP1/2 for destruction, selectively killing BCR-dependent ABC DLBCL cells.


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