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

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 CampoAndreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M. Staudt

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)494-507
Number of pages14
JournalCancer Cell
Volume29
Issue number4
DOIs
StatePublished - Apr 11 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Yang, Y., Kelly, P., Shaffer, A. L., Schmitz, R., Yoo, H. M., Liu, X., Huang, D. W., Webster, D., Young, R. M., Nakagawa, M., Ceribelli, M., Wright, G. W., Yang, Y., Zhao, H., Yu, X., Xu, W., Chan, W. C., Jaffe, E. S., Gascoyne, R. D., ... Staudt, L. M. (2016). Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma. Cancer Cell, 29(4), 494-507. https://doi.org/10.1016/j.ccell.2016.03.006