Skip to main content

Advertisement

SpringerLink
Log in

Neurotrophins and B-cell malignancies

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Neurotrophins and their receptors act as important proliferative and pro-survival factors in a variety of cell types. Neurotrophins are produced by multiple cell types in both pro- and mature forms, and can act in an autocrine or paracrine fashion. The p75NTR and Trk receptors can elicit signalling in response to the presence or absence of their corresponding neurotrophin ligands. This signalling, along with neurotrophin and receptor expression, varies between different cell types. Neurotrophins and their receptors have been shown to be expressed by and elicit signalling in B lymphocytes. In general, most neurotrophins are expressed by activated B-cells and memory B-cells. Likewise, the TrkB95 receptor is seen on activated B-cells, while TrkA and p75NTR are expressed by both resting and active B-cells as well as memory B-cells. Nerve growth factor stimulates B-cell proliferation, memory B-cell survival, antibody production and CD40 expression. Brain-derived neurotrophic factor is involved in B-cell maturation in the bone marrow through TrkB95. Overall neurotrophins and their receptors have been shown to be involved in B-cell proliferation, development, differentiation, antibody secretion and survival. As well as expression and activity in healthy B-cells, the neurotrophins and their receptors can contribute to B-cell malignancies including acute lymphoblastic leukaemia, diffuse large B-cell lymphoma, Burkitt’s lymphoma and multiple myeloma. They are involved in B-cell malignancy survival and potentially in drug resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. LeBien TW, Tedder TF (2008) B lymphocytes: how they develop and function. Blood 112:1570–1580

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Brack C, Hirama M, Lenhardschuller R, Tonegawa S (1978) Complete immunoglobulin gene is created by somatic recombination. Cell 15:1–14

    Article  PubMed  CAS  Google Scholar 

  3. Gathings WE, Lawton AR, Cooper MD (1977) Immunofluorescent studies of development of pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur J Immunol 7:804–810

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Chung JB, Silverman M, Monroe JG (2003) Transitional B cells: step by step towards immune competence. Trends Immunol 24:343–349

    Article  PubMed  CAS  Google Scholar 

  6. Lanzavecchia, A, Bove, S (1985) Specific B lymphocytes efficiently pick up, process and present antigen to T cells. Behring Institute Mitteilungen, pp 82–87

  7. Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354:389–392

    Article  PubMed  CAS  Google Scholar 

  8. Kincade PW, Lawton AR, Bockman DE, Cooper MD (1970) Suppression of immunoglobulin G synthesis as a result of antibody-mediated suppression of immunoglobulin M synthesis in chickens. Proc Natl Acad Sci USA 67:1918–1925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Shapiro-Shelef M, Calame K (2005) Regulation of plasma-cell development. Nat Rev Immunol 5:230–242

    Article  PubMed  CAS  Google Scholar 

  10. McHeyzer-Williams LJ, McHeyzer-Williams MG (2005) Antigen-specific memory B cell development. Annu Rev Immunol 23:487–513

    Article  PubMed  CAS  Google Scholar 

  11. Kehry MR (1996) CD40-mediated signaling in B cells—balancing cell survival, growth, and death. J Immunol 156:2345–2348

    PubMed  CAS  Google Scholar 

  12. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563

    Article  PubMed  CAS  Google Scholar 

  13. Goodnow CC, Adelstein S, Basten A (1990) The need for central and peripheral tolerance in the B cell repertoire. Science 248:1373–1379

    Article  PubMed  CAS  Google Scholar 

  14. Stashenko P, Nadler LM, Hardy R, Schlossman SF (1980) Characterization of a human lymphocyte B specific antigen. Journal of Immunology 125:1678–1685

    CAS  Google Scholar 

  15. Tarlinton D, Radbruch A, Hiepe F, Dorner T (2008) Plasma cell differentiation and survival. Curr Opin Immunol 20:162–169

    Article  PubMed  CAS  Google Scholar 

  16. Shaffer AL, Rosenwald A, Staudt LM (2002) Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2:920–932

    Article  PubMed  CAS  Google Scholar 

  17. Shaffer AL III, Young RM, Staudt LM (2012) Pathogenesis of human B cell lymphomas. Annu Rev Immunol 30(30):565–610

    Article  PubMed  CAS  Google Scholar 

  18. Sabattini E, Bacci F, Sagramoso C, Pileri SA (2010) WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview. Pathologica 102:83–87

    PubMed  CAS  Google Scholar 

  19. Plawny L, Ries F (2014) Emerging new anticancer biological therapies in 2013 (haematological malignancies). Curr Opin Oncol 26:363–370

    Article  PubMed  CAS  Google Scholar 

  20. Plunkett W, Huang P, Gandhi V (1990) Metabolism and action of fludarabine phosphate. Semin Oncol 17:3–17

    PubMed  CAS  Google Scholar 

  21. Rauen HM, Reisch A, Schriewer H (1964) On the biochemical mechanism of action of cyclophosphamide. Arzneimittelforschung 14:176–178

    PubMed  CAS  Google Scholar 

  22. Shaw T, Quan J, Totoritis MC (2003) B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience. Ann Rheum Dis 62(suppl 2):ii55–ii59

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Rudnicka D, Oszmiana A, Finch DK, Strickland I, Schofield DJ, Lowe DC, Sleeman MA, Davis DM (2013) Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity. Blood 121:4694–4702

    Article  PubMed  CAS  Google Scholar 

  24. McLaughlin P, Grillo-Lopez AJ, Maloney DG, Link BK, Levy R, Czuczman MS, Cabanillas F, Dallaire BK, White CA (1998) Efficacy controls and long-term follow-up of patients (pts) treated with rituximab for relapsed or refractory, low-grade or follicular (R-LG/F) NHL. Blood 92:414A–415A

    Google Scholar 

  25. Smith MR (2003) Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 22:7359–7368

    Article  PubMed  CAS  Google Scholar 

  26. Rickert RC (2013) New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 13:578–591

    Article  PubMed  CAS  Google Scholar 

  27. Burger JA (2012) Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape. Curr Opin Oncol 24:643–649

    Article  PubMed  CAS  Google Scholar 

  28. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O’Brien S, Chiorazzi N, Burger JA (2012) The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119:1182–1189

    Article  PubMed  CAS  Google Scholar 

  29. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O’Brien SM (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997–1007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DCS, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park C-M, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19:202–208

    Article  PubMed  CAS  Google Scholar 

  31. Cheadle EJ, Sheard V, Hombach AA, Chmielewski M, Riet T, Berrevoets C, Schooten E, Lamers C, Abken H, Debets R, Gilham DE (2012) Chimeric antigen receptors for T-cell based therapy. Methods Mol Biol (Clifton, N.J.) 907:645–666

    Article  CAS  Google Scholar 

  32. Barrett DM, Singh N, Porter DL, Grupp SA, June CH (2014) Chimeric antigen receptor therapy for cancer. Annu Rev Med 65(65):333–347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Brodie C, Sampson SR (1990) Nerve growth factor and fibroblast growth factor influence postfusion expression of Na channels in cultured rat skeletal muscle. J Cell Physiol 144:492–497

    Article  PubMed  CAS  Google Scholar 

  34. Mayerhofer A, Dissen GA, Parrott JA, Hill DF, Mayerhofer D, Garfield RE, Costa ME, Skinner MK, Ojeda SR (1996) Involvement of nerve growth factor in the ovulatory cascade: trkA receptor activation inhibits gap junctional communication between thecal cells. Endocrinology 137:5662–5670

    PubMed  CAS  Google Scholar 

  35. Levimontalcini R, Hamburger V (1951) Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool 116:321–361

    Article  CAS  Google Scholar 

  36. Levimontalcini R (1964) Nerve growth factor. Ann N Y Acad Sci 118:149–170

    Article  CAS  Google Scholar 

  37. Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1:549–553

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Hohn A, Leibrock J, Bailey K, Barde YA (1990) Identification and characterization of a novel member of the nerve growth factor family. Nature 344:339–341

    Article  PubMed  CAS  Google Scholar 

  39. Jones KR, Reichardt LF (1990) Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci USA 87:8060–8064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hallbook F, Ibanez CF, Persson H (1991) Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in xenopus ovary. Neuron 6:845–858

    Article  PubMed  CAS  Google Scholar 

  41. Berkemeier LR, Winslow JW, Kaplan DR, Nikolics K, Goeddel DV, Rosenthal A (1991) Neurotrophin-5—a novel neurotrophic factor that activates Trk and TrkB. Neuron 7:857–866

    Article  PubMed  CAS  Google Scholar 

  42. Acklin C, Stoney K, Rosenfeld RA, Miller JA, Rohde MF, Haniu M (1993) Recombinant human brain-derived neurotrophic factor (rHuBDNF)—disulfide structure and characterization of BDNF expressed in CHO cells. Int J Pept Protein Res 41:548–552

    Article  PubMed  CAS  Google Scholar 

  43. Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276:12660–12666

    Article  PubMed  CAS  Google Scholar 

  44. Hibbert AP, Morris SJ, Seidah NG, Murphy RA (2003) Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway. J Biol Chem 278:48129–48136

    Article  PubMed  CAS  Google Scholar 

  45. Young M, Oger J, Blanchard MH, Asdourian H, Amos H, Arnason BGW (1975) Secretion of a nerve growth factor by primary chick fibroblast cultures. Science 187:361–362

    Article  PubMed  CAS  Google Scholar 

  46. Hasan W, Pedchenko T, Krizsan-Agbas D, Baum L, Smith PG (2003) Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. J Neurobiol 57:38–53

    Article  PubMed  CAS  Google Scholar 

  47. McDonald NQ, Lapatto R, Murrayrust J, Gunning J, Wlodawer A, Blundell TL (1991) New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature 354:411–414

    Article  PubMed  CAS  Google Scholar 

  48. Jungbluth S, Bailey K, Barde YA (1994) Purification and characterization of a brain-derived neurotrophic factor neurotrophin-3 (BDNF/NT-3) heterodimer. Eur J Biochem 221:677–685

    Article  PubMed  CAS  Google Scholar 

  49. Heymach JV, Shooter EM (1995) The biosynthesis of neurotrophin heterodimers by transfected mammalian cells. J Biol Chem 270:12297–12304

    Article  PubMed  CAS  Google Scholar 

  50. Meakin SO, Shooter EM (1992) The nerve growth factor family of receptors. Trends Neurosci 15:323–331

    Article  PubMed  CAS  Google Scholar 

  51. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848

    Article  PubMed  CAS  Google Scholar 

  52. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75(NTR) and sortilin. J Neurosci 25:5455–5463

    Article  PubMed  CAS  Google Scholar 

  53. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc B Biol Sci 361:1545–1564

    Article  CAS  Google Scholar 

  54. Brennan C, Rivas-Plata K, Landis SC (1999) The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic neurons in vivo. Nat Neurosci 2:699–705

    Article  PubMed  CAS  Google Scholar 

  55. Clewes O, Fahey MS, Tyler SJ, Watson JJ, Seok H, Catania C, Cho K, Dawbarn D, Allen SJ (2008) Human ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin. J Neurochem 107:1124–1135

    PubMed  CAS  Google Scholar 

  56. Boutilier J, Ceni C, Pagdala PC, Forgie A, Neet KE, Barker PA (2008) Proneurotrophins require endocytosis and intracellular proteolysis to induce TrkA activation. J Biol Chem 283:12709–12716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Sobottka B, Reinhardt D, Brockhaus M, Jacobsen H, Metzger F (2008) ProNGF inhibits NGF-mediated TrkA activation in PC12 cells. J Neurochem 107:1294–1303

    Article  PubMed  CAS  Google Scholar 

  58. Demont Y, Corbet C, Page A, Ataman-Onal Y, Choquet-Kastylevsky G, Fliniaux I, Le Bourhis X, Toillon RA, Bradshaw RA, Hondermarck H (2012) Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase A (TrkA) and sortilin protein. J Biol Chem 287:1923–1931

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, Pincelli C (2008) Neurotrophins and their receptors stimulate melanoma cell proliferation and migration. J Investig Dermatol 128:2031–2040

    Article  PubMed  CAS  Google Scholar 

  60. Fayard B, Loeffler S, Weis J, Vogelin E, Kruttgen A (2005) The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res 80:18–28

    Article  PubMed  CAS  Google Scholar 

  61. Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7:148–155

    Article  PubMed  CAS  Google Scholar 

  62. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  PubMed  CAS  Google Scholar 

  63. Klein R, Jing SQ, Nanduri V, Orourke E, Barbacid M (1991) The Trk protooncogene encodes a receptor for nerve growth factor. Cell 65:189–197

    Article  PubMed  CAS  Google Scholar 

  64. Kaplan DR, Stephens RM (1994) Neurotrophin signal transduction by the Trk receptor. J Neurobiol 25:1404–1417

    Article  PubMed  CAS  Google Scholar 

  65. Descamps S, Toillon R, Adriaenssens E, Pawlowski V, Cool S, Nurcombe V, Le Bourhis X, Boilly B, Peyrat J, Hondermarck H (2001) Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J Biol Chem 276:17864–17870

    Article  PubMed  CAS  Google Scholar 

  66. Lagadec C, Meignan S, Adriaenssens E, Foveau B, Vanhecke E, Romon R, Toillon RA, Oxombre B, Hondermarck H, Le Bourhis X (2009) TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene 28:1960–1970

    Article  PubMed  CAS  Google Scholar 

  67. Brodeur GM, Nakagawara A, Yamashiro DJ, Ikegaki N, Liu XG, Azar CG, Lee CP, Evans AE (1997) Expression of TrkA, TrkB and TrkC in human neuroblastomas. J Neurooncol 31:49–55

    Article  PubMed  CAS  Google Scholar 

  68. Perez-Pinera P, Hernandez T, Garcia-Suarez O, de Carlos F, Germana A, del Valle M, Astudillo A, Vega JA (2007) The Trk tyrosine kinase inhibitor K252a regulates growth of lung adenocarcinomas. Mol Cell Biochem 295:19–26

    Article  PubMed  CAS  Google Scholar 

  69. Miknyoczki SJ, Lang D, Huang LY, Klein-Szanto AJP, Dionne CA, Ruggeri BA (1999) Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 81:417–427

    Article  PubMed  CAS  Google Scholar 

  70. Yang X, Martin TA, Jiang WG (2013) Biological influence of brain-derived neurotrophic factor (BDNF) on colon cancer cells. Exp Ther Med 6:1475–1481

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Zhang S, Guo D, Luo W, Zhang Q, Zhang Y, Li C, Lu Y, Cui Z, Qiu X (2010) TrkB is highly expressed in NSCLC and mediates BDNF-induced the activation of Pyk2 signaling and the invasion of A549 cells. BMC Cancer 10:43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Eide FF, Vining ER, Eide BL, Zang KL, Wang XY, Reichardt LF (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123–3129

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426:74–78

    Article  PubMed  CAS  Google Scholar 

  74. Shelton DL, Sutherland J, Gripp J, Camerato T, Armanini MP, Phillips HS, Carroll K, Spencer SD, Levinson AD (1995) Human Trks—molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J Neurosci 15:477–491

    PubMed  CAS  Google Scholar 

  75. Klein R, Conway D, Parada LF, Barbacid M (1990) The TrkB tyrosine protein kinase gene codes for a 2nd neurogenic receptor that lacks the catalytic kinase domain. Cell 61:647–656

    Article  PubMed  CAS  Google Scholar 

  76. Ohira K, Homma KJ, Hirai H, Nakamura S, Hayashi M (2006) TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in glioma cells. Biochem Biophys Res Commun 342:867–874

    Article  PubMed  CAS  Google Scholar 

  77. Kryl D, Barker PA (2000) TTIP is a novel protein that interacts with the truncated T1 TrkB neurotrophin receptor. Biochem Biophys Res Commun 279:925–930

    Article  PubMed  CAS  Google Scholar 

  78. Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233

    Article  PubMed  CAS  Google Scholar 

  79. Liepinsh E, Ilag LL, Otting G, Ibanez CF (1997) NMR structure of the death domain of the p75 neurotrophin receptor. EMBO J 16:4999–5005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Gong Y, Cao P, Yu H-j, Jiang T (2008) Crystal structure of the neurotrophin-3 and p75(NTR) symmetrical complex. Nature 454:789–793

    PubMed  CAS  Google Scholar 

  81. Welcher AA, Bitler CM, Radeke MJ, Shooter EM (1991) Nerve growth factor binding domain of the nerve growth factor receptor. Proc Natl Acad Sci USA 88:159–163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Vilar M, Charalampopoulos I, Kenchappa RS, Simi A, Karaca E, Reversi A, Choi S, Bothwell M, Mingarro I, Friedman WJ, Schiavo G, Bastiaens PIH, Verveer PJ, Carter BD, Ibanez CF (2009) Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers. Neuron 62:72–83

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Khursigara G, Orlinick JR, Chao MV (1999) Association of the p75 neurotrophin receptor with TRAF6. J Biol Chem 274:2597–2600

    Article  PubMed  CAS  Google Scholar 

  84. Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603–614

    Article  PubMed  CAS  Google Scholar 

  85. Allen J, Khwaja F, Byers S, Djakiew D (2005) The p75(NTR) mediates a bifurcated signal transduction cascade through the NF kappa B and JNK pathways to inhibit cell survival. Exp Cell Res 304:69–80

    Article  PubMed  CAS  Google Scholar 

  86. Tsang JYS, Wong KHY, Lai MWH, Lacambra MD, Ko C-W, Chan SK, Lam CCF, Yu AMC, Tan P-H, Tse GM (2012) Nerve growth factor receptor (NGFR): a potential marker for specific molecular subtypes of breast cancer. J Clin Pathol 66:291–296

    Article  PubMed  CAS  Google Scholar 

  87. Krygier S, Djakiew D (2001) Molecular characterization of the loss of p75(NTR) expression in human prostate tumor cells. Mol Carcinog 31:46–55

    Article  PubMed  CAS  Google Scholar 

  88. Rabizadeh S, Oh J, Zhong LT, Yang J, Bitler CM, Butcher LL, Bredesen DE (1993) Induction of apoptosis by the low affinity NGF receptor. Science 261:345–348

    Article  PubMed  CAS  Google Scholar 

  89. Bredesen DE, Ye X, Tasinato A, Sperandio S, Wang JJL, Assa-Munt N, Rabizadeh S (1998) p75(NTR) and the concept of cellular dependence: seeing how the other half die. Cell Death Differ 5:365–371

    Article  PubMed  CAS  Google Scholar 

  90. Coulson EJ, Reid K, Baca M, Shipham KA, Hulett SM, Kilpatrick TJ, Bartlett PF (2000) Chopper, a new death domain of the p75 neurotrophin receptor that mediates rapid neuronal cell death. J Biol Chem 275:30537–30545

    Article  PubMed  CAS  Google Scholar 

  91. Chao MV (1992) Neurotrophin receptors—a window into neuronal differentiation. Neuron 9:583–593

    Article  PubMed  CAS  Google Scholar 

  92. Nikoletopoulou V, Lickert H, Frade JM, Rencurel C, Giallonardo P, Zhang L, Bibel M, Barde Y-A (2010) Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467:59–63

    Article  PubMed  CAS  Google Scholar 

  93. Mehlen P, Rabizadeh S, Snipas SJ, Assa-Munt N, Salvesen GS, Bredesen DE (1998) The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395:801–804

    Article  PubMed  CAS  Google Scholar 

  94. Zupan AA, Johnson EM (1991) Evidence for endocytosis-dependent proteolysis in the generation of soluble truncated nerve growth factor receptors by A875 human melanoma cells. J Biol Chem 266:15384–15390

    PubMed  CAS  Google Scholar 

  95. Tauszig-Delamasure S, Yu L-Y, Cabrera JR, Bouzas-Rodriguez J, Mermet-Bouvier C, Guix C, Bordeaux M-C, Arumae U, Mehlen P (2007) The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm. Proc Natl Acad Sci USA 104:13361–13366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Petersen CM, Nielsen MS, Nykjaer A, Jacobsen L, Tommerup N, Rasmussen HH, Roigaard H, Gliemann J, Madsen P, Moestrup SK (1997) Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem 272:3599–3605

    Article  PubMed  CAS  Google Scholar 

  97. Vega JA, Garcia-Suarez O, Hannestad J, Perez-Perez M, Germana A (2003) Neurotrophins and the immune system. J Anat 203:1–19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Tessarollo L (1998) Pleiotropic functions of neurotrophins in development. Cytokine Growth Factor Rev 9:125–137

    Article  PubMed  CAS  Google Scholar 

  99. Labouyrie E, Parrens M, deMascarel A, Bloch B, Merlio JP (1997) Distribution of NGF receptors in normal and pathologic human lymphoid tissues. J Neuroimmunol 77:161–173

    Article  PubMed  Google Scholar 

  100. Lambiase A, BracciLaudiero L, Bonini S, Starace G, Delios MM, DeCarli M, Aloe L (1997) Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors. J Allergy Clin Immunol 100:408–414

    Article  PubMed  CAS  Google Scholar 

  101. Ehrhard PB, Ganter U, Bauer J, Otten U (1993) Expression of functional Trk protooncogene in human monocytes. Proc Natl Acad Sci USA 90:5423–5427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Boven LA, Middel J, Portegies P, Verhoef J, Jansen GH, Nottet H (1999) Overexpression of nerve growth factor and basic fibroblast growth factor in AIDS dementia complex. J Neuroimmunol 97:154–162

    Article  PubMed  CAS  Google Scholar 

  103. Besser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162:6303–6306

    PubMed  CAS  Google Scholar 

  104. Schober A, Huber K, Fey J, Unsicker K (1998) Distinct populations of macrophages in the adult rat adrenal gland: a subpopulation with neurotrophin-4-like immunoreactivity. Cell Tissue Res 291:365–373

    Article  PubMed  CAS  Google Scholar 

  105. Torcia M, BracciLaudiero L, Lucibello M, Nencioni L, Labardi D, Rubartelli A, Cozzolino F, Aloe L, Garaci E (1996) Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85:345–356

    Article  PubMed  CAS  Google Scholar 

  106. Rosini P, De Chiara G, Lucibello M, Garaci E, Cozzolino F, Torcia M (2000) NGF withdrawal induces apoptosis in CESS B cell line through p38 MAPK activation and Bcl-2 phosphorylation. Biochem Biophys Res Commun 278:753–759

    Article  PubMed  CAS  Google Scholar 

  107. Fauchais A-L, Lalloue F, Lise M-C, Boumediene A, Preud’homme J-L, Vidal E, Jauberteau M-O (2008) Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival. J Immunol 181:3027–3038

    Article  PubMed  CAS  Google Scholar 

  108. D’Onofrio M, de Grazia U, Morrone S, Cuomo L, Spinsanti P, Frati L, Gulino A, Ragona G (2000) Expression of neurotrophin receptors in normal and malignant B lymphocytes. Eur Cytokine Netw 11:283–291

    PubMed  Google Scholar 

  109. Schuhmann B, Dietrich A, Sel S, Hahn C, Klingenspor M, Lommatzsch M, Gudermann T, Braun A, Renz H, Nockher WA (2005) A role for brain-derived neurotrophic factor in B cell development. J Neuroimmunol 163:15–23

    Article  PubMed  CAS  Google Scholar 

  110. Schenone A, Gill JS, Zacharias DA, Windebank AJ (1996) Expression of high- and low-affinity neurotrophin receptors on human transformed B lymphocytes. J Neuroimmunol 64:141–149

    Article  PubMed  CAS  Google Scholar 

  111. Klein G (1994) Epstein-Barr virus strategy in normal and neoplastic B cells. Cell 77:791–793

    Article  PubMed  CAS  Google Scholar 

  112. Franklin RA, Brodie C, Melamed I, Terada N, Lucas JJ, Gelfand EW (1995) Nerve growth factor induces activation of MAP kinase and p90 (RSK) in human B lymphocytes. J Immunol 154:4965–4972

    PubMed  CAS  Google Scholar 

  113. Melamed I, Patel H, Gelfand EW (1997) Trk tyrosine kinase dependent activation of Vav/Ras in human B cells by nerve growth factor. Journal of Allergy and Clinical Immunology 99:1181

    Google Scholar 

  114. Kronfeld I, Kazimirsky G, Gelfand EW, Brodie C (2002) NGF rescues human B lymphocytes from anti-IgM induced apoptosis by activation of PKC zeta. Eur J Immunol 32:136–143

    Article  PubMed  CAS  Google Scholar 

  115. Labouyrie E, Dubus P, Groppi A, Mahon FX, Ferrer J, Parrens M, Reiffers J, de Mascarel A, Merlio JP (1999) Expression of neurotrophins and their receptors in human bone marrow. Am J Pathol 154:405–415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Raoul C, Henderson CE, Pettmann B (1999) Programmed cell death of embryonic motoneurons triggered through the Fas death receptor. J Cell Biol 147:1049–1061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Begum-Haque S, Christy M, Ochoa-Reparaz J, Nowak EC, Mielcarz D, Hague A, Kasper LH (2011) Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J Neuroimmunol 232:136–144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Otten U, Ehrhard P, Peck R (1989) Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci USA 86:10059–10063

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Kimata H, Yoshida A, Ishioka C, Kusunoki T, Hosoi S, Mikawa H (1991) Nerve growth factor specifically induces human IgG4 production. Eur J Immunol 21:137–141

    Article  PubMed  CAS  Google Scholar 

  120. Brodie C, Gelfand EW (1992) Functional nerve growth factor receptors on human B lymphocytes—interaction with IL-2. J Immunol 148:3492–3497

    PubMed  CAS  Google Scholar 

  121. Thorpe LW, Werrbachperez K, Perezpolo JR (1987) Effects of nerve growth factor on the expression of interleukin 2 receptors on cultured human lymphocytes. Ann N Y Acad Sci 496:310–311

    Article  PubMed  CAS  Google Scholar 

  122. Brodie C, Oshiba A, Renz H, Bradley K, Gelfand EW (1996) Nerve growth-factor and anti-CD40 provide opposite signals for the production of IgE in interleukin-4-treated lymphocytes. Eur J Immunol 26:171–178

    Article  PubMed  CAS  Google Scholar 

  123. Abram M, Wegmann M, Fokuhl V, Sonar S, Luger EO, Kerzel S, Radbruch A, Renz H, Zemlin M (2009) Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation. J Immunol 182:4705–4712

    Article  PubMed  CAS  Google Scholar 

  124. Beutel G, Meyer J, Ma LP, Yin SM, Eder M, von Neuhoff N, Wilkens L, Wei J, Hertenstein B, Heil G, Schlegelberger B, Ganser A, Li ZX, Baum C (2005) Expression of the p75 neurotrophin receptor in acute leukaemia. Br J Haematol 131:67–70

    Article  PubMed  CAS  Google Scholar 

  125. Saada S, Marget P, Fauchais AL, Lise MC, Chemin G, Sindou P, Martel C, Delpy L, Vidal E, Jaccard A, Troutaud D, Lalloue F, Jauberteau MO (2012) Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes. J Immunol 189:5293–5303

    Article  PubMed  CAS  Google Scholar 

  126. Bellanger C, Dubanet L, Lise M-C, Fauchais A-L, Bordessoule D, Jauberteau M-O, Troutaud D (2011) Endogenous neurotrophins and Trk signaling in diffuse large B cell lymphoma cell lines are involved in sensitivity to rituximab-induced apoptosis. PLoS One 6:27213

    Article  CAS  Google Scholar 

  127. Sniderhan LF, Garcia-Bates TM, Burgart M, Bernstein SH, Phipps RR, Maggirwar SB (2009) Neurotrophin signaling through tropomyosin receptor kinases contributes to survival and proliferation of non-Hodgkin lymphoma. Exp Hematol 37:1295–1309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Baxter GT, Radeke MJ, Kuo RC, Makrides V, Hinkle B, Hoang R, MedinaSelby A, Coit D, Valenzuela P, Feinstein SC (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17:2683–2690

    PubMed  CAS  Google Scholar 

  129. Pearse RN, Swendeman SL, Li Y, Rafii D, Hempstead BL (2005) A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 105:4429–4436

    Article  PubMed  CAS  Google Scholar 

  130. Xia D, Li W, Zhang L, Qian H, Yao S, Qi X (2014) RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells. Neoplasma 61:523–532

    Article  PubMed  CAS  Google Scholar 

  131. Auffray I, Chevalier S, Froger J, Izac B, Vainchenker W, Gascan H, Coulombel L (1996) Nerve growth factor is involved in the supportive effect by bone marrow-derived stromal cells of the factor-dependent human cell line UT-7. Blood 88:1608–1618

    PubMed  CAS  Google Scholar 

  132. Laurenzi MA, Beccari T, Stenke L, Sjolinder M, Stinchi S, Lindgren JA (1998) Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells—enhanced neurotrophin-4 expression induced by LTB4. J Leukoc Biol 64:228–234

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by Molecular Medicine Ireland as part of the Clinical and Translational Research Scholars Programme.

Author information

Authors and Affiliations

  1. Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland

    Jennifer Hillis, Michael O’Dwyer & Adrienne M. Gorman

  2. Haematology, University College Hospital, Galway, Ireland

    Michael O’Dwyer

Authors
  1. Jennifer Hillis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael O’Dwyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adrienne M. Gorman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adrienne M. Gorman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hillis, J., O’Dwyer, M. & Gorman, A.M. Neurotrophins and B-cell malignancies. Cell. Mol. Life Sci. 73, 41–56 (2016). https://doi.org/10.1007/s00018-015-2046-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-2046-4

Keywords

Search

Navigation