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PMID: 16960154 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL.

Blood ·Vol. 109 ·No. 2 ·2007-01-15 ·Pages 729-39

Chiu A, Xu W, He B, Dillon SR, Gross JA, Sievers E, Qiao X, Santini P, Hyjek E, Lee JW, Cesarman E, Chadburn A, Knowles DM, Cerutti A

Abstract

Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell-derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-kappaB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.

MeSH Terms
B-Cell Activating Factor/metabolism,pharmacology B-Cell Maturation Antigen/biosynthesis,genetics B-Lymphocytes/immunology Cell Line, Tumor Cell Proliferation/drug effects Cell Survival/drug effects Gene Expression Profiling Hodgkin Disease/diagnosis,metabolism,pathology Humans Immunophenotyping RNA Interference Reverse Transcriptase Polymerase Chain Reaction/methods Signal Transduction Transmembrane Activator and CAML Interactor Protein/biosynthesis,genetics Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism,pharmacology
Chemicals
B-Cell Activating Factor B-Cell Maturation Antigen TNFSF13 protein, human TNFSF13B protein, human Transmembrane Activator and CAML Interactor Protein Tumor Necrosis Factor Ligand Superfamily Member 13
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Chiu April
Department of Pathology and Laboratory Medicine, Weill Medical College, Cornell University, 1300 York Ave, Rm C-410, New York, NY 10021, USA.
Xu Weifeng
He Bing
Dillon Stacey R
Gross Jane A
Sievers Eric
Qiao Xugang
Santini Paul
Hyjek Elizabeth
Lee Joong-won
Cesarman Ethel
Chadburn Amy
Knowles Daniel M
Cerutti Andrea
References (74)
74 references, click to expand
  1. BLyS and BLyS receptor expression in non-Hodgkin's lymphoma.
    Exp Hematol. 2002 Feb;30(2):135-41 PMID: 11823048
  2. Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease.
    Blood. 2002 Apr 15;99(8):3060-2 PMID: 11929801
  3. Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells.
    Oncogene. 2002 Apr 11;21(16):2493-503 PMID: 11971184
  4. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL.
    Nat Immunol. 2002 Sep;3(9):822-9 PMID: 12154359
  5. Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival.
    Blood. 2002 Oct 15;100(8):2973-9 PMID: 12351410
  6. An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein.
    EMBO J. 2002 Nov 1;21(21):5711-20 PMID: 12411489
  7. Two pathways to NF-kappaB.
    Mol Cell. 2002 Oct;10(4):693-5 PMID: 12419209
  8. Focus on lymphomas.
    Cancer Cell. 2002 Nov;2(5):363-6 PMID: 12450791
  9. Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays.
    Blood. 2003 Jan 15;101(2):681-9 PMID: 12393683
  10. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
    Blood. 2003 Feb 15;101(4):1505-12 PMID: 12393731
  11. Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas.
    Blood. 2005 Dec 15;106(13):4287-93 PMID: 16123212
  12. Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders.
    J Clin Oncol. 2006 Feb 20;24(6):983-7 PMID: 16432079
  13. An APRIL to remember: novel TNF ligands as therapeutic targets.
    Nat Rev Drug Discov. 2006 Mar;5(3):235-46 PMID: 16474316
  14. HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors.
    J Immunol. 2006 Apr 1;176(7):3931-41 PMID: 16547227
  15. B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia.
    Blood. 2006 Apr 1;107(7):2882-8 PMID: 16304043
  16. Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas.
    Blood. 2006 Jun 1;107(11):4540-8 PMID: 16497967
  17. BAFF AND APRIL: a tutorial on B cell survival.
    Annu Rev Immunol. 2003;21:231-64 PMID: 12427767
  18. Macrophage- and dendritic cell--dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF.
    Blood. 2003 Jun 1;101(11):4464-71 PMID: 12531790
  19. Profiling of Hodgkin's lymphoma cell line L1236 and germinal center B cells: identification of Hodgkin's lymphoma-specific genes.
    Mol Med. 2003 Mar-Apr;9(3-4):85-95 PMID: 12865944
  20. MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival.
    Blood. 2003 Aug 1;102(3):1019-27 PMID: 12689928
  21. EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching.
    J Immunol. 2003 Nov 15;171(10):5215-24 PMID: 14607922
  22. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway.
    Blood. 2004 Jan 15;103(2):679-88 PMID: 14504101
  23. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.
    Blood. 2004 Jan 15;103(2):689-94 PMID: 14512299
  24. BCMA is essential for the survival of long-lived bone marrow plasma cells.
    J Exp Med. 2004 Jan 5;199(1):91-8 PMID: 14707116
  25. TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma.
    J Immunol. 2004 Jan 15;172(2):812-22 PMID: 14707051
  26. Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL.
    J Immunol. 2004 Mar 1;172(5):3268-79 PMID: 14978135
  27. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.
    Blood. 2004 Apr 15;103(8):3148-57 PMID: 15070697
  28. The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers.
    Curr Opin Pharmacol. 2004 Aug;4(4):347-54 PMID: 15251127
  29. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10.
    J Immunol. 2004 Oct 1;173(7):4479-91 PMID: 15383579
  30. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome.
    Blood. 2004 Oct 15;104(8):2247-53 PMID: 15251985
  31. APRIL promotes B-1 cell-associated neoplasm.
    Cancer Cell. 2004 Oct;6(4):399-408 PMID: 15488762
  32. Recent results on the biology of Hodgkin and Reed-Sternberg cells. II. Continuous cell lines.
    Leuk Lymphoma. 1993 Jan;9(1-2):1-25 PMID: 7682880
  33. Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines.
    Blood. 1995 Feb 1;85(3):780-9 PMID: 7530508
  34. BCMAp: an integral membrane protein in the Golgi apparatus of human mature B lymphocytes.
    Int Immunol. 1995 Jul;7(7):1093-106 PMID: 8527407
  35. Peripheral blood mononuclear cells of a patient with advanced Hodgkin's lymphoma give rise to permanently growing Hodgkin-Reed Sternberg cells.
    Blood. 1996 Apr 15;87(8):3418-28 PMID: 8605360
  36. Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling.
    J Clin Invest. 2003 Feb;111(4):529-37 PMID: 12588891
  37. The role of APRIL and BAFF in lymphocyte activation.
    Curr Opin Immunol. 2005 Jun;17(3):282-9 PMID: 15886118
  38. Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation.
    Cell Death Differ. 2005 Jun;12(6):637-48 PMID: 15846369
  39. Expression of BAFF-R (BR 3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody.
    Virchows Arch. 2005 Jul;447(1):53-60 PMID: 16025281
  40. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature.
    Blood. 2005 Aug 1;106(3):1021-30 PMID: 15827134
  41. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha.
    Blood. 2005 Aug 1;106(3):1012-20 PMID: 15860672
  42. TACI is mutant in common variable immunodeficiency and IgA deficiency.
    Nat Genet. 2005 Aug;37(8):829-34 PMID: 16007086
  43. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
    Nat Genet. 2005 Aug;37(8):820-8 PMID: 16007087
  44. NF-kappaB: linking inflammation and immunity to cancer development and progression.
    Nat Rev Immunol. 2005 Oct;5(10):749-59 PMID: 16175180
  45. BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders.
    Hum Pathol. 2005 Oct;36(10):1113-9 PMID: 16226112
  46. Molecular single cell analysis demonstrates the derivation of a peripheral blood-derived cell line (L1236) from the Hodgkin/Reed-Sternberg cells of a Hodgkin's lymphoma patient.
    Blood. 1996 Apr 15;87(8):3429-36 PMID: 8605361
  47. CD30 ligand expression in nonmalignant and Hodgkin's disease-involved lymphoid tissues.
    Am J Pathol. 1996 Aug;149(2):469-81 PMID: 8701986
  48. Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells.
    J Exp Med. 1996 Oct 1;184(4):1495-505 PMID: 8879220
  49. Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.
    Blood. 1996 Nov 1;88(9):3299-305 PMID: 8896393
  50. NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily.
    Science. 1997 Oct 3;278(5335):138-41 PMID: 9311921
  51. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.
    Cell. 1997 Sep 19;90(6):1073-83 PMID: 9323135
  52. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells.
    J Clin Invest. 1997 Dec 15;100(12):2961-9 PMID: 9399941
  53. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.
    Annu Rev Immunol. 1998;16:225-60 PMID: 9597130
  54. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease.
    Annu Rev Immunol. 1998;16:471-93 PMID: 9597138
  55. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth.
    J Exp Med. 1998 Sep 21;188(6):1185-90 PMID: 9743536
  56. Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease.
    Blood. 1998 Oct 1;92(7):2220-8 PMID: 9746758
  57. Somatic mutations within the untranslated regions of rearranged Ig genes in a case of classical Hodgkin's disease as a potential cause for the absence of Ig in the lymphoma cells.
    Blood. 1999 Jun 1;93(11):3964-72 PMID: 10339506
  58. Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1.
    Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17789-94 PMID: 15591344
  59. Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases.
    Blood. 2005 Jan 15;105(2):830-7 PMID: 15358625
  60. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma.
    J Immunol. 2005 Mar 1;174(5):3015-23 PMID: 15728515
  61. Identification of proteoglycans as the APRIL-specific binding partners.
    J Exp Med. 2005 May 2;201(9):1375-83 PMID: 15851487
  62. Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells.
    Blood. 1999 Nov 1;94(9):3129-34 PMID: 10556199
  63. CD30/CD30 ligand and CD40/CD40 ligand in malignant lymphoid disorders.
    Int J Biol Markers. 1999 Jul-Sep;14(3):135-43 PMID: 10569134
  64. Rare occurrence of classical Hodgkin's disease as a T cell lymphoma.
    J Exp Med. 2000 Jan 17;191(2):387-94 PMID: 10637283
  65. Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors.
    Blood. 2000 Feb 15;95(4):1207-13 PMID: 10666192
  66. Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription.
    Blood. 2000 Feb 15;95(4):1443-50 PMID: 10666223
  67. Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease.
    Blood. 2000 May 15;95(10):3020-4 PMID: 10807764
  68. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase.
    J Immunol. 2000 Aug 1;165(3):1322-30 PMID: 10903733
  69. Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor.
    Blood. 2000 Oct 15;96(8):2841-8 PMID: 11023520
  70. Synthesis and release of B-lymphocyte stimulator from myeloid cells.
    Blood. 2001 Jan 1;97(1):198-204 PMID: 11133761
  71. Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription.
    Blood. 2001 Jan 15;97(2):496-501 PMID: 11154228
  72. Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells.
    Blood. 2001 May 1;97(9):2798-807 PMID: 11313274
  73. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase.
    EMBO Rep. 2001 Oct;2(10):945-51 PMID: 11571266
  74. Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines.
    Blood. 2001 Nov 1;98(9):2784-90 PMID: 11675352
Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-04-015958
Published
2007-01-15
Epub
2006-00-07
Pages
729-39
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1785096
Subset
IM
Grants
NIAID NIH HHS · R21 AI057130 · United States
NIAID NIH HHS · R01 AI057530 · United States
NIAID NIH HHS · R01 AI057653 · United States
NIAID NIH HHS · AI057653 · United States
NIAID NIH HHS · AI057530 · United States
NIAID NIH HHS · R01 AI074378 · United States
External Links
PubMed source DOI: 10.1182/blood-2006-04-015958 PMC Full Text View journal details
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