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 Campo; Andreas Rosenwald; German Ott; Jan Delabie; Lisa Rimsza; Louis M. Staudt

doi:10.1016/j.ccell.2016.03.006

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

64 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 language	English (US)
Pages (from-to)	494-507
Number of pages	14
Journal	Cancer cell
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2016.03.006
State	Published - Apr 11 2016

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2016.03.006

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

Yang, Y, Kelly, P, Shaffer, AL, Schmitz, R, Yoo, HM, Liu, X, Huang, DW, Webster, D, Young, RM, Nakagawa, M, Ceribelli, M, Wright, GW, Yang, Y, Zhao, H, Yu, X, Xu, W, Chan, WC, Jaffe, ES, Gascoyne, RD, Campo, E, Rosenwald, A, Ott, G, Delabie, J, Rimsza, L & Staudt, LM 2016, 'Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma', Cancer cell, vol. 29, no. 4, pp. 494-507. https://doi.org/10.1016/j.ccell.2016.03.006

@article{f6b3d012797449c78e601e7287f734ee,

title = "Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma",

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.",

author = "Yibin Yang and Priscilla Kelly and Shaffer, {Arthur L.} and Roland Schmitz and Yoo, {Hee Min} and Xinyue Liu and Huang, {Da Wei} and Daniel Webster and Young, {Ryan M.} and Masao Nakagawa and Michele Ceribelli and Wright, {George W.} and Yandan Yang and Hong Zhao and Xin Yu and Weihong Xu and Chan, {Wing C.} and Jaffe, {Elaine S.} and Gascoyne, {Randy D.} and Elias Campo and Andreas Rosenwald and German Ott and Jan Delabie and Lisa Rimsza and Staudt, {Louis M.}",

note = "Funding Information: The authors thank the patients for their participation. We wish to thank Kathleen Meyer for her assistance with GEO submissions, and the members of the Coriell Genotyping and Microarray Center for their assistance with Affymetrix SNP6.0 array. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). This research was supported by the Intramural Research Program of the NIH , National Cancer Institute , Center for Cancer Research . R.S. was supported by the Dr. Mildred Scheel Stiftung f{\"u}r Krebsforschung (Deutsche Krebshilfe). D.W. is the Philip O'Bryan Montgomery, Jr., MD, Fellow of the Damon Runyon Cancer Research Foundation (DRG-2208-14). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = apr,

day = "11",

doi = "10.1016/j.ccell.2016.03.006",

language = "English (US)",

volume = "29",

pages = "494--507",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma

AU - Yang, Yibin

AU - Kelly, Priscilla

AU - Shaffer, Arthur L.

AU - Schmitz, Roland

AU - Yoo, Hee Min

AU - Liu, Xinyue

AU - Huang, Da Wei

AU - Webster, Daniel

AU - Young, Ryan M.

AU - Nakagawa, Masao

AU - Ceribelli, Michele

AU - Wright, George W.

AU - Yang, Yandan

AU - Zhao, Hong

AU - Yu, Xin

AU - Xu, Weihong

AU - Chan, Wing C.

AU - Jaffe, Elaine S.

AU - Gascoyne, Randy D.

AU - Campo, Elias

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Rimsza, Lisa

AU - Staudt, Louis M.

N1 - Funding Information: The authors thank the patients for their participation. We wish to thank Kathleen Meyer for her assistance with GEO submissions, and the members of the Coriell Genotyping and Microarray Center for their assistance with Affymetrix SNP6.0 array. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). This research was supported by the Intramural Research Program of the NIH , National Cancer Institute , Center for Cancer Research . R.S. was supported by the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). D.W. is the Philip O'Bryan Montgomery, Jr., MD, Fellow of the Damon Runyon Cancer Research Foundation (DRG-2208-14). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/4/11

Y1 - 2016/4/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84962685404&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962685404&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.03.006

DO - 10.1016/j.ccell.2016.03.006

M3 - Article

C2 - 27070702

AN - SCOPUS:84962685404

SN - 1535-6108

VL - 29

SP - 494

EP - 507

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this