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Oncogenically active MYD88 mutations in human lymphoma

Abstract

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.

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Figure 1: MYD88 is required for survival of ABC DLBCL cells.
Figure 2: MYD88 mutations in human lymphomas.
Figure 3: MYD88 mutations are gain-of-function.
Figure 4: MYD88 mutants activate NF-κB and cytokine signalling.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression profiling data have been submitted to GEO under accession number GSE22900.

References

  1. 1

    Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008)

    CAS  Article  Google Scholar 

  2. 2

    Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Ishii, K. J. & Akira, S. Innate immune recognition of, and regulation by, DNA. Trends Immunol. 27, 525–532 (2006)

    CAS  Article  Google Scholar 

  4. 4

    Lenz, G. & Staudt, L. M. Aggressive lymphomas. N. Engl. J. Med. 362, 1417–1429 (2010)

    CAS  Article  Google Scholar 

  5. 5

    Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Kato, M. et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 459, 712–716 (2009)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010)

    ADS  CAS  Article  Google Scholar 

  9. 9

    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)

    CAS  Article  Google Scholar 

  10. 10

    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)

    CAS  Article  Google Scholar 

  11. 11

    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)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000)

    ADS  CAS  Article  Google Scholar 

  13. 13

    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)

    CAS  Article  Google Scholar 

  14. 14

    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)

    ADS  CAS  Article  Google Scholar 

  15. 15

    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)

    ADS  CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    Shaffer, A. L. et al. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol. Rev. 210, 67–85 (2006)

    CAS  Article  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    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)

    CAS  Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    Staudt, L. M. Oncogenic activation of NF-κB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010)

    Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

  24. 24

    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)

    CAS  Article  Google Scholar 

  25. 25

    Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Schmidlin, H., Diehl, S. A. & Blom, B. New insights into the regulation of human B-cell differentiation. Trends Immunol. 30, 277–285 (2009)

    CAS  Article  Google Scholar 

  27. 27

    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)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

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V.N.N., R.M.Y., R.S., S.J., K.-H.L., H.K. and A.L.S. designed and performed experiments. W.X., Y.Y. and H.Z. performed experiments. W.X., G.W. and J.P. analysed data. A.R., H.K.M.-H., G.O., R.D.G., J.M.C., L.M.R., E.C., E.S.J., J.D., E.B.S., R.I.F., R.M.B., R.R.T., J.R.C., D.D.W. and W.C.C. supplied patient samples and reviewed pathological and clinical data. L.M.S. designed and supervised research and wrote the manuscript.

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Correspondence to Louis M. Staudt.

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The authors declare no competing financial interests.

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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

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