title: Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance.
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.
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, 2 Australian Phenomics Facility, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: James Q
authors.initials: JQ
authors.lastname: Wang
authors.forename: Yogesh S
authors.initials: YS
authors.lastname: Jeelall
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horikawa
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division / Q000276:immunology; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics*; D007160:Immunoproliferative Disorders / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C052617:Bcl2 protein, mouse; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse