Synergistic cooperation and crosstalk between MYD88L265P and mutations that dysregulate CD79B and surface IgM

James Q. Wang, Yogesh S. Jeelall, Peter Humburg, Emma L. Batchelor, Sarp M. Kaya, Hee Min Yoo, Christopher C. Goodnow*, Keisuke Horikawa

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    33 Citations (Scopus)

    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 MYD88L265P 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 MYD88L265P 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 MYD88L265P. In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P 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 MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.

    Original languageEnglish
    Pages (from-to)2759-2776
    Number of pages18
    JournalJournal of Experimental Medicine
    Volume214
    Issue number9
    DOIs
    Publication statusPublished - 2017

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