Review Article | Published:

Malignant pirates of the immune system

Nature Immunology volume 12, pages 933940 (2011) | Download Citation

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.

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References

  1. 1.

    & Aggressive lymphomas. N. Engl. J. Med. 362, 1417–1429 (2010).

  2. 2.

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

  3. 3.

    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).

  4. 4.

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

  5. 5.

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

  6. 6.

    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).

  7. 7.

    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).

  8. 8.

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

  9. 9.

    , & Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

  10. 10.

    , , , & Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997).

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    , , , & 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).

  19. 19.

    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).

  20. 20.

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

  21. 21.

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

  22. 22.

    , & Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32, 606–613 (2002).

  23. 23.

    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).

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

    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).

  28. 28.

    , , & IRF4: Immunity. Malignancy! Therapy? Clin. Cancer Res. 15, 2954–2961 (2009).

  29. 29.

    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).

  30. 30.

    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).

  31. 31.

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

  32. 32.

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

  33. 33.

    , , & 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).

  34. 34.

    et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl. Acad. Sci. USA 105, 13520–13525 (2008).

  35. 35.

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

  36. 36.

    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).

  37. 37.

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

  38. 38.

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

  39. 39.

    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).

  40. 40.

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

  41. 41.

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

  42. 42.

    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).

  43. 43.

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

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 48.

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

  49. 49.

    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).

  50. 50.

    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).

  51. 51.

    , , , & PTEN gene alterations in lymphoid neoplasms. Blood 92, 3410–3415 (1998).

  52. 52.

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

  53. 53.

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

  54. 54.

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

  55. 55.

    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).

  56. 56.

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

  57. 57.

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

  58. 58.

    , , & Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb. Perspect. Biol. 2, a003004 (2010).

  59. 59.

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

  60. 60.

    & 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).

  61. 61.

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

  62. 62.

    , , & Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain. Biochemistry 49, 8240–8250 (2010).

  63. 63.

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

  64. 64.

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

  65. 65.

    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).

  66. 66.

    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).

  67. 67.

    , & 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).

  68. 68.

    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).

  69. 69.

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

  70. 70.

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

  71. 71.

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

  72. 72.

    , , & Nuclear factor kB is required for the development of marginal zone B lymphocytes. J. Exp. Med. 192, 1175–1182 (2000).

  73. 73.

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

  74. 74.

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

  75. 75.

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

  76. 76.

    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).

  77. 77.

    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).

  78. 78.

    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).

  79. 79.

    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).

  80. 80.

    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).

  81. 81.

    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).

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

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

  85. 85.

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

  86. 86.

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

  87. 87.

    , , & The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity 30, 44–55 (2009).

  88. 88.

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

  89. 89.

    , , , & 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).

  90. 90.

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

  91. 91.

    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).

  92. 92.

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

  93. 93.

    , & Molecular underpinning of B-cell anergy. Immunol. Rev. 237, 249–263 (2010).

  94. 94.

    , , , & Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J. Immunol. 182, 5382–5392 (2009).

  95. 95.

    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).

  96. 96.

    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).

  97. 97.

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

  98. 98.

    et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc. Natl. Acad. Sci. USA 103, 10961–10966 (2006).

  99. 99.

    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).

  100. 100.

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

  101. 101.

    , & The human thymus contains a novel population of B lymphocytes. Lancet 2, 1488–1491 (1987).

  102. 102.

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

  103. 103.

    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).

  104. 104.

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

  105. 105.

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

  106. 106.

    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).

  107. 107.

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

  108. 108.

    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).

  109. 109.

    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).

  110. 110.

    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).

  111. 111.

    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).

  112. 112.

    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).

  113. 113.

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

  114. 114.

    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).

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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.).

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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

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Louis M Staudt.

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

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