Sci. Signal., 8 February 2011
Lymphoma Oncogenic MyD88
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
The activated B cell–like (ABC) subtype is the least responsive to therapy of the diffuse large B cell lymphomas (DLBCLs). DLBCL is the most common form of aggressive lymphoma. ABC DLBCLs are characterized by constitutive activity of nuclear factor B (NF-B), with a subset of these lymphomas also exhibiting synergistic activation of NF-B by the Janus-activated kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) pathway. Ngo et al. performed an RNA interference (RNAi) screen for genes required for the survival and proliferation of lymphoma cell lines. They found that knockdown of the gene encoding myeloid differentiation marker 88 (MyD88), an adaptor protein that mediates activation of NF-B by Toll-like receptors (TLRs), substantially reduced the viability of ABC DLBCL cell lines but not that of other DLBCL subtypes. Knockdown of the gene encoding interleukin-1 receptor (IL-1R)–associated kinase 1 (IRAK1), a serine and threonine kinase that is recruited to MyD88, had a similar effect to knockdown of MyD88 on ABC DLBCL cell line survival. Sequencing revealed a single nucleotide variant, which mutated Leu265 to proline, in the coding region of MyD88 in the ABC DLBCL cell lines. Of almost 400 ABC DLBCL biopsy samples screened, 29% had the same L265P mutation. Reconstitution of ABC DLBCL cell lines with MyD88 L265P, but not wild-type MyD88, rescued the survival defect caused by knockdown of MyD88. Analysis of gene expression profiles showed overlap between the genes activated in ABC DLBCL cells expressing MyD88 L265P and those characteristic of NF-B and JAK-STAT3 signaling. Knockdown of MyD88 in some ABC DLBCL cell lines inhibited the secretion of IL-6 and IL-10, which can stimulate STAT3 signaling in an autocrine manner. Together, these data suggest that constitutive MyD88-dependent signaling is required for the survival of a subset of ABC DLBCLs and that components of MyD88 signaling might provide therapeutic targets.
V. N. Ngo, R. M. Young, R. Schmitz, S. Jhavar, W. Xiao, K.-H. Lim, H. Kohlhammer, W. Xu, Y. Yang, H. Zhao, A. L. Shaffer, P. Romesser, G. Wright, J. Powell, A. Rosenwald, H. K. Muller-Hermelink, G. Ott, R. D. Gascoyne, J. M. Connors, L. M. Rimsza, E. Campo, E. S. Jaffe, J. Delabie, E. B. Smeland, R. I. Fisher, R. M. Braziel, R. R. Tubbs, J. R. Cook, D. D. Weisenburger, W. C. Chan, L. M. Staudt, Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011). [PubMed]
Citation: J. F. Foley, Oncogenic MyD88. Sci. Signal. 4, ec37 (2011).
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