Consequences of the recurrent MYD88L265P somatic mutation for B cell tolerance

James Q. Wang, Yogesh S. Jeelall, Bruce Beutler, Keisuke Horikawa, Christopher C. Goodnow

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

MYD88L265P has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenström's macroglobulinemia, and diffuse large B cell lymphoma. In this study, we analyze the consequences for antigen-activated primary B cells of acquiring MYD88L265P. The mutation induced rapid B cell division in the absence of exogenous TLR ligands and was inhibited by Unc93b13d mutation and chloroquine or TLR9 deficiency, indicating continued dependence on upstream TLR9 activation. Proliferation and NF-κB activation induced by MYD88L265P were nevertheless rapidly countered by the induction of TNFAIP3, an NF-κB inhibitor frequently inactivated in MYD88L265P-bearing lymphomas, and extinguished by Bim-dependent apoptosis. MYD88L265P caused self-reactive B cells to accumulate in vivo only when apoptosis was opposed by Bcl2 overexpression. These results reveal checkpoints that fortify TLR responses against aberrant B cell proliferation in response to ubiquitous TLR and BCR self-ligands and suggest that tolerance failure requires the accumulation of multiple somatic mutations.

Original languageEnglish (US)
Pages (from-to)413-426
Number of pages14
JournalJournal of Experimental Medicine
Volume211
Issue number3
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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