The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy1. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling2,3, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008)
Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010)
Ishii, K. J. & Akira, S. Innate immune recognition of, and regulation by, DNA. Trends Immunol. 27, 525–532 (2006)
Lenz, G. & Staudt, L. M. Aggressive lymphomas. N. Engl. J. Med. 362, 1417–1429 (2010)
Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008)
Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009)
Kato, M. et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 459, 712–716 (2009)
Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010)
Lam, L. T. et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma. Blood 111, 3701–3713 (2008)
Ding, B. B. et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 111, 1515–1523 (2008)
Lin, S. C., Lo, Y. C. & Wu, H. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885–890 (2010)
Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000)
Li, C., Zienkiewicz, J. & Hawiger, J. Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1β signaling pathway. J. Biol. Chem. 280, 26152–26159 (2005)
Lenz, G. et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl Acad. Sci. USA 105, 13520–13525 (2008)
Jiang, Z. et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc. Natl Acad. Sci. USA 103, 10961–10966 (2006)
Yamin, T. T. & Miller, D. K. The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J. Biol. Chem. 272, 21540–21547 (1997)
Powers, J. P. et al. Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4. Bioorg. Med. Chem. Lett. 16, 2842–2845 (2006)
Shaffer, A. L. et al. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol. Rev. 210, 67–85 (2006)
Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001)
Dierlamm, J. et al. Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 11, 747–758 (1997)
Novak, U. et al. The NF-κB negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone B-cell lymphomas. Blood 113, 4918–4921 (2009)
Staudt, L. M. Oncogenic activation of NF-κB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010)
Milhollen, M. A. et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-κB-dependent lymphoma. Blood 116, 1515–1523 (2010)
Lam, L. T. et al. Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11, 28–40 (2005)
Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006)
Schmidlin, H., Diehl, S. A. & Blom, B. New insights into the regulation of human B-cell differentiation. Trends Immunol. 30, 277–285 (2009)
Schmitz, R. et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J. Exp. Med. 206, 981–989 (2009)
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, an NCI SPECS grant (UO1-CA 114778), and by the Foundation for NIH, through a gift from the Richard A. Lauderbaugh Memorial Fund. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). R.S. is supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). P.R. was an HHMI-NIH Research Scholar. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). We thank D. Staudt for discussions, K. Meyer for help with the GEO submission, and X. Li for IRAK1 plasmids. We are grateful to B. Tran and the Center for Cancer Research Sequencing Facility for implementation of next generation RNA sequencing.
The authors declare no competing financial interests.
The file contains Supplementary Figures 1-3 and an additional reference. (PDF 462 kb)
The file contains Supplementary Table 1 (XLS 48 kb)
The file contains Supplementary Table 2 (XLS 73 kb)
The file contains Supplementary Table 3 (XLS 2959 kb)
The file contains Supplementary Table 4 (XLS 49 kb)
The file contains Supplementary Table 5 (XLS 8862 kb)
About this article
Cite this article
Ngo, V., Young, R., Schmitz, R. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011). https://doi.org/10.1038/nature09671
TLR‐MyD88 signaling blockades inhibit refractory B‐1b cell immune responses to transplant‐related glycan antigens
American Journal of Transplantation (2021)
Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells
Frontiers in Oncology (2021)
Targeted In Vivo Delivery of NF-κB Decoy Inhibitor Augments Sensitivity of B Cell Lymphoma to Therapy
Molecular Therapy (2021)
Molecular Immunology (2021)