Mutations in the IgG B cell receptor associated with class-switched B cell lymphomas

Abstract

Immunoglobulin class-switching from IgM to IgG enhances B cell receptor (BCR) signalling1,2 and promotes germinal centre (GC) B cell responses to antigens3,4. In contrast, non-Hodgkin lymphomas derived from GC B cells typically avoid IgG BCR expression and retain the unswitched IgM BCR, suggesting that the IgG BCR may protect B cells from malignant transformation5,6. However, the mechanism of this phenomenon and its significance for the pathogenicity of IgG-expressing lymphomas remains unclear. Here, we report that IgG-positive follicular lymphoma (FL) and the related EZB subset of diffuse large B cell lymphoma (DLBCL) acquire mutations in the IgG heavy chain, disrupting its unique intracellular tail. Enforced class switching of IgM-expressing EZB DLBCL cell lines to IgG reduces BCR surface levels, signalling via phosphoinositide-3 kinase (PI3K), levels of MYC, cell proliferation and in vivo growth. Inhibiting GSK3, a target of BCR-PI3K signalling, or stimulating the BCR rescues IgG+ cell proliferation. In contrast, IgG tail-truncating mutations enhance BCR surface expression, intracellular signalling and competitive growth. These findings suggest that the expansion of IgG-switched GC-like B lymphoma cells is limited by low tonic PI3K activity of the wild-type IgG BCR, but a subset of these cancers acquires mutations of the IgG intracellular tail that reverse this effect, promoting the oncogenicity of their BCRs. The presence of IgG tail mutations underscores the importance of isotype-specific BCR signalling in the pathogenesis of FL and EZB DLBCL and can potentially inform therapeutic targeting with BCR signalling inhibitors or antibody-drug conjugates.