Poster Presentation 30th Lorne Cancer Conference 2018

Oncogenic MYD88 mutations, the dark side of B cell development (#173)

James Wang , Sarp Kaya , Christopher Goodnow , Keisuke Horikawa

MYD88 is a critical adaptor protein that transmits signals through Toll-like receptors (TLRs) and IL-1/18 receptors. Genome-wide sequencing of B cell malignancies identified recurrent somatic mutations in MYD88 in 40% of all diffuse large B cell lymphoma (DLBCL) and 90% of Waldenström macroglobulinemia (WM). We have investigated the consequences of the frequently occurring oncogenic mutation, MYD88 L265P in mouse primary B cell models. Interestingly, retroviral gene transduction of the MYD88L265P mutation into normal activated B cells drives mitogen-independent B cell proliferation both in vitro and in vivo. B cell overproliferation induced by MYD88L265P was countered by Bim-dependent apoptosis and inhibition of NF-κB activation, due in part to the induction of TNFAIP3. Intriguingly, MYD88L265P-driven B cell proliferation was repressed by chloroquine, UNC93B3d mutation, or TLR9 deficiency, indicating that MYD88L265P is not a constitutively active oncogene and requires a correctly localized DNA-sensing TLR9 to promote B cell proliferation in culture. However, when transplanted into Rag1-deficient mice, paradoxically MYD88L265P-expressing B cells with defective endosomal TLRs expanded more than control B cells and differentiated into IgM-secreting plasmablasts or plasma cells. Finally, MYD88L265P induced plasma cell differentiation in cooperation with CD79B mutations, which are commonly and frequently detected together with MYD88L265P in DLBCL and WM. Thus, MYD88L265P cooperates with genetic variants in other signalling pathways to transform B cells into malignant cells.