A multiprotein supercomplex controlling oncogenic signalling in lymphoma

James D. Phelan, Ryan M. Young, Daniel E. Webster, Sandrine Roulland, George W. Wright, Monica Kasbekar, Arthur L. Shaffer, Michele Ceribelli, James Q. Wang, Roland Schmitz, Masao Nakagawa, Emmanuel Bachy, Da Wei Huang, Yanlong Ji, Lu Chen, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Maryknoll M. Palisoc & 20 others Racquel R. Valadez, Theresa Davies-Hill, Wyndham H. Wilson, Wing C. Chan, Elaine S. Jaffe, Randy D. Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Fausto J. Rodriguez, Fayez Estephan, Matthias Holdhoff, Michael J. Kruhlak, Stephen M. Hewitt, Craig J. Thomas, Stefania Pittaluga, Thomas Oellerich, Louis M. Staudt

Research output: Contribution to journalLetter

29 Citations (Scopus)

Abstract

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11–BCL10–MALT1 adaptor complex, which recruits and activates IκB kinase4–6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR–Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

Original languageEnglish (US)
Pages (from-to)387-391
Number of pages5
JournalNature
Volume560
Issue number7718
DOIs
StatePublished - Aug 16 2018

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Lymphoma
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
T-Cell Antigen Receptor
Mutation
Genome
Germinal Center
Toll-Like Receptors
Autoantigens
Gene Expression Profiling
B-Cell Lymphoma
Proteomics
Neoplasms
Protein Isoforms
Phosphotransferases
PCI 32765
Clinical Trials

ASJC Scopus subject areas

  • General

Cite this

Phelan, J. D., Young, R. M., Webster, D. E., Roulland, S., Wright, G. W., Kasbekar, M., ... Staudt, L. M. (2018). A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature, 560(7718), 387-391. https://doi.org/10.1038/s41586-018-0290-0

A multiprotein supercomplex controlling oncogenic signalling in lymphoma. / Phelan, James D.; Young, Ryan M.; Webster, Daniel E.; Roulland, Sandrine; Wright, George W.; Kasbekar, Monica; Shaffer, Arthur L.; Ceribelli, Michele; Wang, James Q.; Schmitz, Roland; Nakagawa, Masao; Bachy, Emmanuel; Huang, Da Wei; Ji, Yanlong; Chen, Lu; Yang, Yandan; Zhao, Hong; Yu, Xin; Xu, Weihong; Palisoc, Maryknoll M.; Valadez, Racquel R.; Davies-Hill, Theresa; Wilson, Wyndham H.; Chan, Wing C.; Jaffe, Elaine S.; Gascoyne, Randy D.; Campo, Elias; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa; Rodriguez, Fausto J.; Estephan, Fayez; Holdhoff, Matthias; Kruhlak, Michael J.; Hewitt, Stephen M.; Thomas, Craig J.; Pittaluga, Stefania; Oellerich, Thomas; Staudt, Louis M.

In: Nature, Vol. 560, No. 7718, 16.08.2018, p. 387-391.

Research output: Contribution to journalLetter

Phelan, JD, Young, RM, Webster, DE, Roulland, S, Wright, GW, Kasbekar, M, Shaffer, AL, Ceribelli, M, Wang, JQ, Schmitz, R, Nakagawa, M, Bachy, E, Huang, DW, Ji, Y, Chen, L, Yang, Y, Zhao, H, Yu, X, Xu, W, Palisoc, MM, Valadez, RR, Davies-Hill, T, Wilson, WH, Chan, WC, Jaffe, ES, Gascoyne, RD, Campo, E, Rosenwald, A, Ott, G, Delabie, J, Rimsza, L, Rodriguez, FJ, Estephan, F, Holdhoff, M, Kruhlak, MJ, Hewitt, SM, Thomas, CJ, Pittaluga, S, Oellerich, T & Staudt, LM 2018, 'A multiprotein supercomplex controlling oncogenic signalling in lymphoma', Nature, vol. 560, no. 7718, pp. 387-391. https://doi.org/10.1038/s41586-018-0290-0
Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018 Aug 16;560(7718):387-391. https://doi.org/10.1038/s41586-018-0290-0
Phelan, James D. ; Young, Ryan M. ; Webster, Daniel E. ; Roulland, Sandrine ; Wright, George W. ; Kasbekar, Monica ; Shaffer, Arthur L. ; Ceribelli, Michele ; Wang, James Q. ; Schmitz, Roland ; Nakagawa, Masao ; Bachy, Emmanuel ; Huang, Da Wei ; Ji, Yanlong ; Chen, Lu ; Yang, Yandan ; Zhao, Hong ; Yu, Xin ; Xu, Weihong ; Palisoc, Maryknoll M. ; Valadez, Racquel R. ; Davies-Hill, Theresa ; Wilson, Wyndham H. ; Chan, Wing C. ; Jaffe, Elaine S. ; Gascoyne, Randy D. ; Campo, Elias ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Rimsza, Lisa ; Rodriguez, Fausto J. ; Estephan, Fayez ; Holdhoff, Matthias ; Kruhlak, Michael J. ; Hewitt, Stephen M. ; Thomas, Craig J. ; Pittaluga, Stefania ; Oellerich, Thomas ; Staudt, Louis M. / A multiprotein supercomplex controlling oncogenic signalling in lymphoma. In: Nature. 2018 ; Vol. 560, No. 7718. pp. 387-391.
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abstract = "B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11–BCL10–MALT1 adaptor complex, which recruits and activates IκB kinase4–6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37{\%} of cases of ABC1. The most striking response rate (80{\%}) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR–Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.",
author = "Phelan, {James D.} and Young, {Ryan M.} and Webster, {Daniel E.} and Sandrine Roulland and Wright, {George W.} and Monica Kasbekar and Shaffer, {Arthur L.} and Michele Ceribelli and Wang, {James Q.} and Roland Schmitz and Masao Nakagawa and Emmanuel Bachy and Huang, {Da Wei} and Yanlong Ji and Lu Chen and Yandan Yang and Hong Zhao and Xin Yu and Weihong Xu and Palisoc, {Maryknoll M.} and Valadez, {Racquel R.} and Theresa Davies-Hill and Wilson, {Wyndham H.} 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 Rodriguez, {Fausto J.} and Fayez Estephan and Matthias Holdhoff and Kruhlak, {Michael J.} and Hewitt, {Stephen M.} and Thomas, {Craig J.} and Stefania Pittaluga and Thomas Oellerich and Staudt, {Louis M.}",
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T1 - A multiprotein supercomplex controlling oncogenic signalling in lymphoma

AU - Phelan, James D.

AU - Young, Ryan M.

AU - Webster, Daniel E.

AU - Roulland, Sandrine

AU - Wright, George W.

AU - Kasbekar, Monica

AU - Shaffer, Arthur L.

AU - Ceribelli, Michele

AU - Wang, James Q.

AU - Schmitz, Roland

AU - Nakagawa, Masao

AU - Bachy, Emmanuel

AU - Huang, Da Wei

AU - Ji, Yanlong

AU - Chen, Lu

AU - Yang, Yandan

AU - Zhao, Hong

AU - Yu, Xin

AU - Xu, Weihong

AU - Palisoc, Maryknoll M.

AU - Valadez, Racquel R.

AU - Davies-Hill, Theresa

AU - Wilson, Wyndham H.

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 - Rodriguez, Fausto J.

AU - Estephan, Fayez

AU - Holdhoff, Matthias

AU - Kruhlak, Michael J.

AU - Hewitt, Stephen M.

AU - Thomas, Craig J.

AU - Pittaluga, Stefania

AU - Oellerich, Thomas

AU - Staudt, Louis M.

PY - 2018/8/16

Y1 - 2018/8/16

N2 - B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11–BCL10–MALT1 adaptor complex, which recruits and activates IκB kinase4–6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR–Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

AB - B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11–BCL10–MALT1 adaptor complex, which recruits and activates IκB kinase4–6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR–Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

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