Synergistic cooperation and crosstalk between MYD88 ^L265P and mutations that dysregulate CD79B and surface IgM

Abstract

Wang et al. show cooperation between MYD88 ^L265P and CD79B mutations dysregulating B cell responses to self-antigen and differentiation into plasma cells. Their results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against MYD88 ^L265P , explaining the co-occurrence of MYD88 and CD79B mutations in human lymphomas.

Abstract

CD79B and MYD88 mutations 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 of CD79B and MYD88 ^L265P mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88 ^L265P decreased 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 of MYD88 ^L265P . In B cells chronically stimulated by self-antigen, CD79B and MYD88 ^L265P mutations 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 by MYD88 ^L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.