| First Author | Wang JQ | Year | 2014 |
| Journal | J Exp Med | Volume | 211 |
| Issue | 3 | Pages | 413-26 |
| PubMed ID | 24534189 | Mgi Jnum | J:210476 |
| Mgi Id | MGI:5571236 | Doi | 10.1084/jem.20131424 |
| Citation | Wang JQ, et al. (2014) Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance. J Exp Med 211(3):413-26 |
| abstractText | MYD88(L265P) has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenstrom'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-kappaB activation induced by MYD88(L265P) were nevertheless rapidly countered by the induction of TNFAIP3, an NF-kappaB 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. |
