Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms

Yibin Yang, Roland Schmitz, Joseph Mitala, Amanda Whiting, Wenming Xiao, Michele Ceribelli, George W. Wright, Hong Zhao, Yandan Yang, Weihong Xu, Andreas Rosenwald, German Ott, Randy D. Gascoyne, Joseph M. Connors, Lisa M. Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Rita BrazielRaymond R. Tubbs, James R. Cook, Dennis D. Weisenburger, Wing C. Chan, Adrian Wiestner, Michael J. Kruhlak, Kazuhiro Iwai, Federico Bernal, Louis M. Staudt

Research output: Contribution to journalArticle

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Abstract

Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target. SIGNIFICANCE: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis.

Original languageEnglish (US)
Pages (from-to)480-493
Number of pages14
JournalCancer Discovery
Volume4
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Polyubiquitin
Ubiquitin
Lymphoma
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
Credentialing
Proteins
B-Cell Lymphoma
Ligases
Molecular Biology
Cell Survival
Phosphotransferases
Therapeutics
Peptides

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Yang, Y., Schmitz, R., Mitala, J., Whiting, A., Xiao, W., Ceribelli, M., ... Staudt, L. M. (2014). Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discovery, 4(4), 480-493. https://doi.org/10.1158/2159-8290.CD-13-0915

Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. / Yang, Yibin; Schmitz, Roland; Mitala, Joseph; Whiting, Amanda; Xiao, Wenming; Ceribelli, Michele; Wright, George W.; Zhao, Hong; Yang, Yandan; Xu, Weihong; Rosenwald, Andreas; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Braziel, Rita; Tubbs, Raymond R.; Cook, James R.; Weisenburger, Dennis D.; Chan, Wing C.; Wiestner, Adrian; Kruhlak, Michael J.; Iwai, Kazuhiro; Bernal, Federico; Staudt, Louis M.

In: Cancer Discovery, Vol. 4, No. 4, 2014, p. 480-493.

Research output: Contribution to journalArticle

Yang, Y, Schmitz, R, Mitala, J, Whiting, A, Xiao, W, Ceribelli, M, Wright, GW, Zhao, H, Yang, Y, Xu, W, Rosenwald, A, Ott, G, Gascoyne, RD, Connors, JM, Rimsza, LM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Braziel, R, Tubbs, RR, Cook, JR, Weisenburger, DD, Chan, WC, Wiestner, A, Kruhlak, MJ, Iwai, K, Bernal, F & Staudt, LM 2014, 'Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms', Cancer Discovery, vol. 4, no. 4, pp. 480-493. https://doi.org/10.1158/2159-8290.CD-13-0915
Yang, Yibin ; Schmitz, Roland ; Mitala, Joseph ; Whiting, Amanda ; Xiao, Wenming ; Ceribelli, Michele ; Wright, George W. ; Zhao, Hong ; Yang, Yandan ; Xu, Weihong ; Rosenwald, Andreas ; Ott, German ; Gascoyne, Randy D. ; Connors, Joseph M. ; Rimsza, Lisa M. ; Campo, Elias ; Jaffe, Elaine S. ; Delabie, Jan ; Smeland, Erlend B. ; Braziel, Rita ; Tubbs, Raymond R. ; Cook, James R. ; Weisenburger, Dennis D. ; Chan, Wing C. ; Wiestner, Adrian ; Kruhlak, Michael J. ; Iwai, Kazuhiro ; Bernal, Federico ; Staudt, Louis M. / Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. In: Cancer Discovery. 2014 ; Vol. 4, No. 4. pp. 480-493.
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T1 - Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms

AU - Yang, Yibin

AU - Schmitz, Roland

AU - Mitala, Joseph

AU - Whiting, Amanda

AU - Xiao, Wenming

AU - Ceribelli, Michele

AU - Wright, George W.

AU - Zhao, Hong

AU - Yang, Yandan

AU - Xu, Weihong

AU - Rosenwald, Andreas

AU - Ott, German

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Rimsza, Lisa M.

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Braziel, Rita

AU - Tubbs, Raymond R.

AU - Cook, James R.

AU - Weisenburger, Dennis D.

AU - Chan, Wing C.

AU - Wiestner, Adrian

AU - Kruhlak, Michael J.

AU - Iwai, Kazuhiro

AU - Bernal, Federico

AU - Staudt, Louis M.

PY - 2014

Y1 - 2014

N2 - Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target. SIGNIFICANCE: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis.

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