Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance

J Exp Med. 2014 Mar 10;211(3):413-26. doi: 10.1084/jem.20131424. Epub 2014 Feb 17.

Abstract

MYD88(L265P) 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 MYD88(L265P). The mutation induced rapid B cell division in the absence of exogenous TLR ligands and was inhibited by Unc93b1(3d) mutation and chloroquine or TLR9 deficiency, indicating continued dependence on upstream TLR9 activation. Proliferation and NF-κB activation induced by MYD88(L265P) were nevertheless rapidly countered by the induction of TNFAIP3, an NF-κB inhibitor frequently inactivated in MYD88(L265P)-bearing lymphomas, and extinguished by Bim-dependent apoptosis. MYD88(L265P) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Blotting, Western
  • Cell Division / immunology
  • Cell Proliferation
  • Cysteine Endopeptidases / metabolism
  • Gene Expression Regulation / immunology*
  • Gene Rearrangement, B-Lymphocyte / genetics
  • Immune Tolerance / genetics*
  • Immunoproliferative Disorders / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation, Missense / genetics
  • Myeloid Differentiation Factor 88 / genetics*
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • Proto-Oncogene Proteins c-vav / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Intracellular Signaling Peptides and Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-vav
  • Vav1 protein, mouse
  • Bcl2 protein, mouse
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse