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.

在B细胞恶性肿瘤中经常并同时检测到CD79B和MYD88突变。尚不清楚这些突变是否协同作用或如何发生串扰。在这里，我们分析了CD79B和MYD88 ^L265P突变的后果，并结合了正常激活的小鼠B淋巴细胞。单独的CD79B突变可增加表面IgM，但不能增强B细胞存活，增殖或改变NF-κB响应标记。相反，表达MYD88 ^L265P的B细胞降低的表面IgM加上内切糖苷酶H敏感的IgM在细胞内的积累，类似于自身抗原反复刺激的无反应B细胞中的运输阻滞。CD79B的突变或过表达抵消了MYD88 ^L265P的作用。在由自身抗原长期刺激的B细胞中，CD79B和MYD88 ^L265P突变组合但非单独结合，阻断了外周缺失并触发了分化为分泌自身抗体的浆母细胞。这些结果表明，CD79B和表面IgM构成了针对MYD88 ^L265P对B细胞失调的限速检查点，并为MYD88和淋巴瘤中的CD79B突变。