A multiprotein supercomplex controlling oncogenic signalling in lymphoma.
Nature. 2018 Jun 20;:
Authors: 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 LM, Rodriguez FJ, Estephan F, Holdhoff M, Kruhlak MJ, Hewitt SM, Thomas CJ, Pittaluga S, Oellerich T, Staudt LM
B cell receptor (BCR) signaling 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 DLBCL subtypes, known as germinal center (GC) B cell-like (GCB) and activated B cell-like (ABC)2,3, with inferior outcomes following immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11-BCL10-MALT1 (CBM) adapter complex that recruits and activates IκB kinase (IKK)4-6. Genome sequencing revealed gain-of-function mutations targeting the CD79A and CD79B BCR subunits and the Toll-like receptor (TLR) signaling adapter MYD885,7, with MYD88L265P being the most prevalent isoform. In a clinical trial, the BTK inhibitor, ibrutinib, produced responses in 37% of ABC cases1. The most striking response rate (80%) was observed in tumors with both CD79B and MYD88L265P mutations, but how these mutations cooperate to promote dependence on BCR signaling remains unclear. Herein, we used genome-wide CRISPR-Cas9 screening and functional proteomics to understand the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9, and the BCR (My-T-BCR). The My-T-BCR co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signaling. Inhibitors of BCR and mTOR signaling cooperatively decreased My-T-BCR supercomplex formation and function, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR complexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a roadmap for the rational deployment of oncogenic signaling inhibitors in molecularly-defined subsets of DLBCL.
PMID: 29925955 [PubMed - as supplied by publisher]