A multiprotein supercomplex controlling oncogenic signalling in lymphoma.
2018
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–
MALT1adaptor complex, which recruits and activates IκB kinase4–6. Genome sequencing revealed gain-of-function mutations that target the
CD79Aand
CD79BBCR 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
ibrutinibproduced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both
CD79Band MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR–
Cas9screening 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,
TLR9and 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
ibrutinibresponders 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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