Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Malignant pirates of the immune system

Nature Immunology volume 12, pages 933–940 (2011)Cite this article

Subjects

Abstract

At great human cost, cancer is the largest genetic experiment ever conducted. This review highlights how lymphoid malignancies have genetically perverted normal immune signaling and regulatory mechanisms for their selfish oncogenic goals of unlimited proliferation, perpetual survival and evasion of the immune response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Origin of human lymphoid malignancies.
Figure 2
Figure 3: Oncogenic MYD88 mutations in human lymphomas and leukemias activate multiple downstream signaling pathways.
Figure 4: Model for the pathogenesis of PMBL and Hodgkin lymphoma.

Similar content being viewed by others

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    CAS  PubMed  Google Scholar 

  3. Wright, G. et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA 100, 9991–9996 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dave, S.S. et al. Molecular diagnosis of Burkitt's lymphoma. N. Engl. J. Med. 354, 2431–2442 (2006).

    CAS  PubMed  Google Scholar 

  5. Cattoretti, G. et al. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107, 3967–3975 (2006).

    CAS  PubMed  Google Scholar 

  6. Savage, K.J. et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102, 3871–3879 (2003).

    CAS  PubMed  Google Scholar 

  7. Rosenwald, A. et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198, 851–862 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bergsagel, P.L. et al. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc. Natl. Acad. Sci. USA 93, 13931–13936 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Luo, J., Solimini, N.L. & Elledge, S.J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dent, A.L., Shaffer, A.L., Yu, X., Allman, D. & Staudt, L.M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997).

    CAS  PubMed  Google Scholar 

  11. Ye, B.H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat. Genet. 16, 161–170 (1997).

    CAS  PubMed  Google Scholar 

  12. Fukuda, T. et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J. Exp. Med. 186, 439–448 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ye, B.H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large- cell lymphoma. Science 262, 747–750 (1993).

    CAS  PubMed  Google Scholar 

  14. Cattoretti, G. et al. BCL-6 protein is expressed in germinal-center B cells. Blood 86, 45–53 (1995).

    CAS  PubMed  Google Scholar 

  15. Cattoretti, G. et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7, 445–455 (2005).

    CAS  PubMed  Google Scholar 

  16. Shaffer, A.L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    CAS  PubMed  Google Scholar 

  17. Tunyaplin, C. et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173, 1158–1165 (2004).

    CAS  PubMed  Google Scholar 

  18. Phan, R.T., Saito, M., Basso, K., Niu, H. & Dalla-Favera, R. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nat. Immunol. 6, 1054–1060 (2005).

    CAS  PubMed  Google Scholar 

  19. Ranuncolo, S.M. et al. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nat. Immunol. 8, 705–714 (2007).

    CAS  PubMed  Google Scholar 

  20. Phan, R.T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bereshchenko, O.R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32, 606–613 (2002).

    CAS  PubMed  Google Scholar 

  23. Saito, M. et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA 106, 11294–11299 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ci, W. et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B-cells and is deregulated in DLBCL. Blood (2009).

  25. Polo, J.M. et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat. Med. 10, 1329–1335 (2004).

    CAS  PubMed  Google Scholar 

  26. Cerchietti, L.C. et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 17, 400–411 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Falini, B. et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 95, 2084–2092 (2000).

    CAS  PubMed  Google Scholar 

  28. Shaffer, A.L., Emre, N.C., Romesser, P.B. & Staudt, L.M. IRF4: Immunity. Malignancy! Therapy? Clin. Cancer Res. 15, 2954–2961 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007).

    CAS  PubMed  Google Scholar 

  30. 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  PubMed  Google Scholar 

  31. Mittrücker, H.W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).

    PubMed  Google Scholar 

  32. Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).

    CAS  PubMed  Google Scholar 

  33. Davis, R.E., Brown, K.D., Siebenlist, U. & Staudt, L.M. Constitutive nuclear factor kB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203, 311–317 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Mandelbaum, J. et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell 18, 568–579 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tam, W. et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107, 4090–4100 (2006).

    CAS  PubMed  Google Scholar 

  38. Schmidlin, H. et al. Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression. Blood 112, 1804–1812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Iqbal, J. et al. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 21, 2332–2343 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kallies, A. et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J. Exp. Med. 200, 967–977 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 26, 555–566 (2007).

    CAS  PubMed  Google Scholar 

  42. Calado, D.P. et al. Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell 18, 580–589 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shaffer, A.L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  46. Ngo, V.N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  49. 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  PubMed  PubMed Central  Google Scholar 

  50. Novak, U. et al. The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone B-cell lymphomas. Blood 113, 4918–4921 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sakai, A., Thieblemont, C., Wellmann, A., Jaffe, E.S. & Raffeld, M. PTEN gene alterations in lymphoid neoplasms. Blood 92, 3410–3415 (1998).

    CAS  PubMed  Google Scholar 

  52. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kloo, B. et al. Critical role of PI3K signaling for NF-κB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. Proc. Natl. Acad. Sci. USA 108, 272–277 (2011).

    CAS  PubMed  Google Scholar 

  56. Yang, J. et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkB. Genes Dev. 21, 1396–1408 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Thome, M., Charton, J.E., Pelzer, C. & Hailfinger, S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb. Perspect. Biol. 2, a003004 (2010).

    PubMed  PubMed Central  Google Scholar 

  59. Sommer, K. et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005).

    CAS  PubMed  Google Scholar 

  60. McCully, R.R. & Pomerantz, J.L. The protein kinase C-responsive inhibitory domain of CARD11 functions in NF-κB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association. Mol. Cell. Biol. 28, 5668–5686 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bidère, N. et al. Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009).

    PubMed  Google Scholar 

  62. Lamason, R.L., McCully, R.R., Lew, S.M. & Pomerantz, J.L. Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain. Biochemistry 49, 8240–8250 (2010).

    CAS  PubMed  Google Scholar 

  63. Coornaert, B. et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nat. Immunol. 9, 263–271 (2008).

    CAS  PubMed  Google Scholar 

  64. Rebeaud, F. et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat. Immunol. 9, 272–281 (2008).

    CAS  PubMed  Google Scholar 

  65. Hailfinger, S. et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. USA 106, 19946–19951 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ferch, U. et al. Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 206, 2313–2320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhou, H., Du, M.Q. & Dixit, V.M. Constitutive NF-κB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 7, 425–431 (2005).

    CAS  PubMed  Google Scholar 

  68. Gyrd-Hansen, M. et al. IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis. Nat. Cell Biol. 10, 1309–1317 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rosebeck, S. et al. Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-κB activation. Science 331, 468–472 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lam, K.P., Kuhn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

    CAS  PubMed  Google Scholar 

  71. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cariappa, A., Liou, H.C., Horwitz, B.H. & Pillai, S. Nuclear factor kB is required for the development of marginal zone B lymphocytes. J. Exp. Med. 192, 1175–1182 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat. Rev. Immunol. 4, 348–359 (2004).

    CAS  PubMed  Google Scholar 

  74. Bahler, D.W. & Levy, R. Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc. Natl. Acad. Sci. USA 89, 6770–6774 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Fais, F. et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J. Clin. Invest. 102, 1515–1525 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Messmer, B.T. et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J. Exp. Med. 200, 519–525 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chu, C.C. et al. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 115, 3907–3915 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Hervé, M. et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J. Clin. Invest. 115, 1636–1643 (2005).

    PubMed  PubMed Central  Google Scholar 

  79. Herishanu, Y. et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117, 563–574 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Vaandrager, J.W. et al. DNA fiber fluorescence in situ hybridization analysis of immunoglobulin class switching in B-cell neoplasia: aberrant CH gene rearrangements in follicle center-cell lymphoma. Blood 92, 2871–2878 (1998).

    CAS  PubMed  Google Scholar 

  81. Lossos, I.S. et al. Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. Proc. Natl. Acad. Sci. USA 97, 10209–10213 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lenz, G. et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med. 204, 633–643 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ruminy, P. et al. The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma. Leukemia 25, 681–688 (2011).

    CAS  PubMed  Google Scholar 

  84. Engels, N. & Wienands, J. The signaling tool box for tyrosine-based costimulation of lymphocytes. Curr. Opin. Immunol. 23, 324–329 (2011).

    CAS  PubMed  Google Scholar 

  85. Martin, S.W. & Goodnow, C.C. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat. Immunol. 3, 182–188 (2002).

    CAS  PubMed  Google Scholar 

  86. Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009).

    CAS  PubMed  Google Scholar 

  87. Tolar, P., Hanna, J., Krueger, P.D. & Pierce, S.K. The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity 30, 44–55 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rolli, V. et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol. Cell 10, 1057–1069 (2002).

    CAS  PubMed  Google Scholar 

  89. Chan, V.W., Meng, F., Soriano, P., DeFranco, A.L. & Lowell, C.A. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity 7, 69–81 (1997).

    CAS  PubMed  Google Scholar 

  90. Gazumyan, A., Reichlin, A. & Nussenzweig, M.C. Igβ tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization. J. Exp. Med. 203, 1785–1794 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ma, H. et al. Visualization of Syk-antigen receptor interactions using green fluorescent protein: differential roles for Syk and Lyn in the regulation of receptor capping and internalization. J. Immunol. 166, 1507–1516 (2001).

    CAS  PubMed  Google Scholar 

  92. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    CAS  PubMed  Google Scholar 

  93. Yarkoni, Y., Getahun, A. & Cambier, J.C. Molecular underpinning of B-cell anergy. Immunol. Rev. 237, 249–263 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gross, A.J., Lyandres, J.R., Panigrahi, A.K., Prak, E.T. & DeFranco, A.L. Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J. Immunol. 182, 5382–5392 (2009).

    CAS  PubMed  Google Scholar 

  95. 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  PubMed  PubMed Central  Google Scholar 

  96. 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  PubMed  PubMed Central  Google Scholar 

  97. Puente, X.S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hou, B. et al. Selective utilization of Toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity 34, 375–384 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Marshak-Rothstein, A. & Rifkin, I.R. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25, 419–441 (2007).

    CAS  PubMed  Google Scholar 

  101. Isaacson, P.G., Norton, A.J. & Addis, B.J. The human thymus contains a novel population of B lymphocytes. Lancet 2, 1488–1491 (1987).

    CAS  PubMed  Google Scholar 

  102. Rui, L. et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18, 590–605 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Skinnider, B.F. et al. Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99, 618–626 (2002).

    CAS  PubMed  Google Scholar 

  104. Shi, S. et al. JAK signaling globally counteracts heterochromatic gene silencing. Nat. Genet. 38, 1071–1076 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Dawson, M.A. et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461, 819–822 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Green, M.R. et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116, 3268–3277 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Steidl, C. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Yap, D.B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Morin, R.D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Sneeringer, C.J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. USA 107, 20980–20985 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Calin, G.A. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 99, 15524–15529 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Klein, U. et al. The DLEU2/miR-15a/16–1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17, 28–40 (2010).

    CAS  PubMed  Google Scholar 

  113. Tiacci, E. et al. BRAF mutations in hairy-cell leukemia. N. Engl. J. Med. 364, 2305–2315 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Irish, J.M. et al. B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression. Proc. Natl. Acad. Sci. USA 107, 12747–12754 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe; R.S.) and the National Health and Medical Research Council of Australia (L.R.).

Author information

Authors and Affiliations

  1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Lixin Rui, Roland Schmitz, Michele Ceribelli & Louis M Staudt

Authors
  1. Lixin Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roland Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michele Ceribelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louis M Staudt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Louis M Staudt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rui, L., Schmitz, R., Ceribelli, M. et al. Malignant pirates of the immune system. Nat Immunol 12, 933–940 (2011). https://doi.org/10.1038/ni.2094

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2094

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer