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Nature. 2018 Aug;560(7718):387-391. doi: 10.1038/s41586-018-0290-0. Epub 2018 Jun 20.

A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

Author information

1
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
Aix-Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
3
Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
4
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Gaithersburg, MD, USA.
5
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.
6
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
7
Departments of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
8
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
9
Hospital Clinic, University of Barcelona, Barcelona, Spain.
10
Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
11
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.
12
University Health Network, Laboratory Medicine Program, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada.
13
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA.
14
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
15
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
16
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
17
Experimental Pathology Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
18
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. thomas.oellerich@kgu.de.
19
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany. thomas.oellerich@kgu.de.
20
German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany. thomas.oellerich@kgu.de.
21
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. lstaudt@mail.nih.gov.

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.

PMID:
29925955
PMCID:
PMC6201842
DOI:
10.1038/s41586-018-0290-0
[Indexed for MEDLINE]
Free PMC Article

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