Poster Presentation 28th Lorne Cancer Conference 2016

Over 30% of activated B cell type diffuse large B cell lymphomas (ABC-DLBCLs) and 90% of Waldenström macroglobulinaemia (WM) patients have the MYD88^L265P mutation. Since MYD88 is an adaptor protein downstream of Toll-like receptors (TLRs) and the transmembrane activator and CAML interactor (TACI) for BAFF, we investigate the potential for targeting these pathways for MYD88^L265P lymphomas. We transduced mature B cells from wild type, Unc93b1^3d mutant or Tlr9 deficient mice with retroviral constructs encoding the MYD88^L265P mutation, and analysed their proliferation when placed in tissue culture or adoptively transferred into mice. The disruption of endosomal TLRs by the Unc93b1^3d mutation or Tlr9 deficiency suppressed MYD88^L265P B cell proliferation in vitro. However, the same disruptions to endosomal TLRs failed to prevent MYD88^L265P B cell growth in vivo, and instead promoted MYD88^L265P B cell differentiation into B220^lowCD19^low plasmablasts. Interestingly, the addition of BAFF rescued the in vitro proliferation defect of Tlr9 deficient MYD88^L265P B cells. Furthermore, Tlr9 deficient MYD88^L265P B cells failed to persist in vivo in the absence of BAFF. Our results demonstrated a paradoxical effect of blocking endosomal TLRs for MYD88^L265P B cells and suggest a role for BAFF in malignant B cell expansion. Our findings shed new light on TLR and BAFF as activators for MYD88^L265P B cell proliferation and thus potential therapeutic targets for treating MYD88^L265P lymphomas.