Synergistic cooperation and crosstalk betweenMYD88L265Pand mutations that dysregulate CD79B and surface IgM

Abstract

CD79B andMYD88mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences ofCD79BandMYD88L265Pmutations individually and combined in normal activated mouse B lymphocytes.CD79Bmutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressingMYD88L265Pdecreased surface IgM coupled with accumulation of endoglycosidase H-sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect ofMYD88L265PIn B cells chronically stimulated by self-antigen,CD79BandMYD88L265Pmutations in combination, but not individually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation byMYD88L265Pand provide an explanation for the co-occurrence ofMYD88andCD79Bmutations in lymphomas.