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