Skip to main content
SpringerLink
Log in

Cytokines and Soluble Molecules in CLL

  • Chapter
Chronic Lymphocytic Leukemia

Part of the book series: Contemporary Hematology ((CH))

Abstract

The pathogenesis of B-cell chronic lymphocytic leukemia (CLL) and the mechanisms regulating the growth, survival, and expansion of the leukemic clone are still largely unknown, but there is growing evidence of the important role played by cytokine networks and soluble mediators in the leukemic process. Leukemic CLL cells represent the most prominent population in CLL, but not the only one. Accessory non-neoplastic hematopoietic cells circulate in the peripheral blood and bone marrow of CLL patients, and cells of stromal origin are in strict contact with the tumor clone. The crosstalk between all these cell populations is mediated by soluble factors that may influence the pattern of survival and expansion of the disease, as well as the function of the normal compartment. The peculiar and in many ways unique clinical picture of CLL is likely to arise from the complex interactions of different networks, in which the action of one cytokine may strongly influence the production of, and response to, another. In the present chapter we discuss the role that different cytokines and soluble molecules may play, alone or through complex interactions, both on the leukemic clone and on the clinical course of the disease. For the sake of clarity, we discuss separately cytokines that induce cell survival, inhibitory cytokines, and soluble molecules.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andreeff M, Darzynkiewicz Z, Sharpless TK, Clarkson BD, Melamed MR. Discrimination of human leukemia subtypes by flow cytometric analysis of cellular DNA and RNA. Blood 1980; 55: 282–293.

    PubMed  CAS  Google Scholar 

  2. Jurlander J. The cellular biology of B-cell chronic lymphocytic leukemia. Crit Rev Oncol Hematol 1998; 27: 29–52.

    Article  PubMed  CAS  Google Scholar 

  3. Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet 1995; 11: 69–74.

    Article  PubMed  CAS  Google Scholar 

  4. Auron PE, Webb AC, Rosenwasser LJ, et al. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 1984; 81: 7907–7911.

    Article  PubMed  CAS  Google Scholar 

  5. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996; 87: 2095–2147.

    PubMed  CAS  Google Scholar 

  6. Hurme M, Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1 Ra and IL-]beta genes. Eur J Immunol 1998; 28: 2598–2602.

    Article  PubMed  CAS  Google Scholar 

  7. Pistoia V, Cozzolino F, Rubartelli A, Torcia M, Roncella S, Ferrarini M. In vitro production of interleukin 1 by normal and malignant human B-lymphocytes. J Immunol 1986; 136: 1688–1692.

    PubMed  CAS  Google Scholar 

  8. Morabito F, Prasthofer EF, Dunlap NE, Grossi CE, Tilden AB. Expression of myelomonocytic antigens on chronic lymphocytic leukemia B-cells correlates with their ability to produce interleukin 1. Blood 1987; 70: 1750–1757.

    PubMed  CAS  Google Scholar 

  9. Uggla C, Aguilar-Santelises M, Rosen A, Mellstedt H, Jondal M. Spontaneous production of interleukin 1 activity by chronic lymphocytic leukemic cells. Blood 1987; 70: 1851–1857.

    PubMed  CAS  Google Scholar 

  10. Plate JM, Knospe WH, Harris JE, Gregory SA. Normal and aberrant expression of cytokines in neoplastic cells from chronic lymphocytic leukemias. Hum Immunol 1993; 36: 249–258.

    Article  PubMed  CAS  Google Scholar 

  11. Jewell AP, Lydyard PM, Worman CP, Giles FJ, Goldstone AH. Growth factors can protect B-chronic lymphocytic leukaemia cells against programmed cell death without stimulating proliferation. Leuk Lymphoma 1995; 18: 159–162.

    Article  PubMed  CAS  Google Scholar 

  12. Aguilar-Santelises M, Amador JF, Mellstedt H, Jondal M. Low IL-1 beta production in leukemic cells from progressive B cell chronic leukemia (B-CLL). Leuk Res 1989; 13: 937–942.

    Article  PubMed  CAS  Google Scholar 

  13. Hulkkonen J, Vilpo J, Vilpo L, Koski T, Hurme M. Interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-6 plasma levels and cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic parameters. Haematologica 2000; 85: 600–606.

    PubMed  CAS  Google Scholar 

  14. Smith KA. Interleukin-2: inception, impact, and implications. Science 1988; 240: 1169–1176.

    Article  PubMed  CAS  Google Scholar 

  15. Theze J, Alzari PM, Bertoglio J. Interleukin 2 and its receptors: recent advances and new immunological functions. Immunol Today 1996; 17: 481–486.

    Article  PubMed  CAS  Google Scholar 

  16. de Totero D, Francia di Celle P, Cignetti A, Foa R. The IL-2 receptor complex: expression and function on normal and leukemic B-cells. Leukemia 1995; 9: 1425–1431.

    PubMed  Google Scholar 

  17. Lantz O, Grillot-Courvalin C, Schmitt C, Fermand JP, Brouet JC. Interleukin 2-induced proliferation of leukemic human B-cells. J Exp Med 1985; 161: 1225–1230.

    Article  PubMed  CAS  Google Scholar 

  18. Fluckiger AC, Rossi JF, Bussel A, Bryon P, Banchereau J, Defrance T. Responsiveness of chronic lymphocytic leukemia B-cells activated via surface Igs or CD40 to B-cell tropic factors. Blood 1992; 80: 3173–3181.

    PubMed  CAS  Google Scholar 

  19. Mainou-Fowler T, Copplestone JA, Prentice AG. Effect of interleukins on the proliferation and survival of B cell chronic lymphocytic leukaemia cells. J Clin Pathol 1995; 48: 482–487.

    Article  PubMed  CAS  Google Scholar 

  20. Foa R, Giovarelli M, Jemma C, et al. Interleukin 2 (IL 2) and interferon-gamma production by T-lymphocytes from patients with B-chronic lymphocytic leukemia: evidence that normally released IL 2 is absorbed by the neoplastic B cell population. Blood 1985; 66: 614–619.

    PubMed  CAS  Google Scholar 

  21. Semenzato G, Foa R, Agostini C, et al. High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. Blood 1987; 70: 396–400.

    PubMed  CAS  Google Scholar 

  22. Callea V, Morabito F, Luise F, et al. Clinical significance of sIL2R, sCD23, sICAM-1, IL6 and sCD14 serum levels in B-cell chronic lymphocytic leukemia. Haematologica 1996; 81: 310–315.

    PubMed  CAS  Google Scholar 

  23. Foa R, Fierro MT, Giovarelli M, et al. Immunoregulatory T-cell defects in B-cell chronic lymphocytic leukemia: cause or consequence of the disease? The contributory role of decreased availability of interleukin 2 (IL-2). Blood Cells 1987; 12: 399–412.

    PubMed  CAS  Google Scholar 

  24. Bartik MM, Welker D, Kay NE. Impairments in immune cell function in B cell chronic lymphocytic leukemia. Semin Oncol 1998; 25: 27–33.

    PubMed  CAS  Google Scholar 

  25. Howard M, Farrar J, Hilfiker M, et al. Identification of a T cell-derived B cell growth factor distinct from interleukin 2. J Exp Med 1982; 155: 914–923.

    Article  PubMed  CAS  Google Scholar 

  26. Banchereau J, Bidaud C, Fluckiger AC, et al. Effects of interleukin 4 on human B-cell growth and differentiation. Res Immunol 1993; 144: 601–605.

    Article  PubMed  CAS  Google Scholar 

  27. Llorente L, Mitjavila F, Crevon MC, Galanaud P. Dual effects of interleukin 4 on antigen-activated human B-cells: induction of proliferation and inhibition of interleukin 2-dependent differentiation. Eur J Immunol 1990; 20: 1887–1892.

    Article  PubMed  CAS  Google Scholar 

  28. Karray S, DeFrance T, Merle-Beral H, Banchereau J, Debre P, Galanaud P. Interleukin 4 counteracts the interleukin 2-induced proliferation of monoclonal B-cells. J Exp Med 1988; 168: 85–94.

    Article  PubMed  CAS  Google Scholar 

  29. van Kooten C, Rensink I, Aarden L, van Oers R. Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells. Blood 1992; 80: 1299–1306.

    PubMed  Google Scholar 

  30. Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B-cells from death by apoptosis and upregulates Bc1–2 expression. J Exp Med 1992; 176: 1319–1326.

    Article  PubMed  CAS  Google Scholar 

  31. Mainou-Fowler T, Craig VA, Copplestone AJ, Hamon MD, Prentice AG. Effect of anti-APO 1 on spontaneous apoptosis of B-cells in chronic lymphocytic leukaemia: the role of bc1–2 and interleukin 4. Leuk Lymphoma 1995; 19: 301–308.

    Article  PubMed  CAS  Google Scholar 

  32. Tangye SG, Raison RL. Human cytokines suppress apoptosis of leukaemic CD5+ B-cells and preserve expression of bcl-2. Immunol Cell Biol 1997; 75: 127–135.

    Article  PubMed  CAS  Google Scholar 

  33. Frankfurt OS, Byrnes JJ, Villa L. Protection from apoptotic cell death by interleukin-4 is increased in previously treated chronic lymphocytic leukemia patients. Leuk Res 1997; 21: 9–16.

    Article  PubMed  CAS  Google Scholar 

  34. de Totero D, Reato G, Mauro F, et al. IL4 production and increased CD30 expression by a unique CD8+ T-cell subset in B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 104: 589–599.

    Article  PubMed  Google Scholar 

  35. Reyes E, Prieto A, Carrion F, et al. Altered pattern of cytokine production by peripheral blood CD2+ cells from B chronic lymphocytic leukemia patients. Am J Hematol 1998; 57: 93–100.

    Article  PubMed  CAS  Google Scholar 

  36. Mainou-Fowler T, Miller S, Proctor SJ, Dickinson AM. The levels of TNF alpha, IL4 and IL10 production by T-cells in B-cell chronic lymphocytic leukaemia (B-CLL). Leuk Res 2001; 25: 157–163.

    Article  PubMed  CAS  Google Scholar 

  37. Kay NE, Han L, Bone N, Williams G. Interleukin 4 content in chronic lymphocytic leukaemia (CLL) B-cells and blood CD8+ T-cells from B-CLL patients: impact on clonal B-cell apoptosis. Br J Haematol 2001; 112: 760–767.

    Article  PubMed  CAS  Google Scholar 

  38. Lundin J, Kimby E, Bergmann L, Karakas T, Mellstedt H, Osterborg A. Interleukin 4 therapy for patients with chronic lymphocytic leukaemia: a phase VII study. Br J Haematol 2001; 112: 155–160.

    Article  PubMed  CAS  Google Scholar 

  39. Kishimoto T. The biology of interleukin-6. Blood 1989; 74: 1–10.

    PubMed  CAS  Google Scholar 

  40. Hsu SM, Xie SS, Waldron JA Jr. Functional heterogeneity and pathogenic significance of interleukin-6 in B-cell lymphomas. Am J Pathol 1992; 141: 915–923.

    PubMed  CAS  Google Scholar 

  41. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol 1995; 13: 575–582.

    PubMed  CAS  Google Scholar 

  42. Aderka D, Maor Y, Novick D, et al. Interleukin-6 inhibits the proliferation of B-chronic lymphocytic leukemia cells that is induced by tumor necrosis factor-alpha or -beta. Blood 1993; 81: 2076–2084.

    PubMed  CAS  Google Scholar 

  43. Reittie JE, Yong KL, Panayiotidis P, Hoffbrand AV. Interleukin-6 inhibits apoptosis and tumour necrosis factor induced proliferation of B-chronic lymphocytic leukaemia. Leuk Lymphoma 1996; 22: 83–90.

    Article  PubMed  CAS  Google Scholar 

  44. Bussing A, Stein GM, Stumpf C, Schietzel M. Release of interleukin-6 in cultured B-chronic lymphocytic leukaemia cells is associated with both activation and cell death via apoptosis. Anticancer Res 1999; 19: 3953–3959.

    PubMed  CAS  Google Scholar 

  45. Brown PD, Diamant M, Jensen PO, Geisler CH, Mortensen BT, Nissen NI. S-phase induction by interleukin6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. Leuk Lymphoma 1999; 34: 325–333.

    PubMed  CAS  Google Scholar 

  46. Moreno A, Villar ML, Camara C, et al. Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells. Blood 2001; 97: 242–249.

    Article  PubMed  CAS  Google Scholar 

  47. Panayiotidis P, Jones D, Ganeshaguru K, Foroni L, Hoffbrand AV. Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol 1996; 92: 97–103.

    Article  PubMed  CAS  Google Scholar 

  48. Lagneaux L, Delforge A, Bron D, DeBruyn C, Stryckmans P. Chronic lymphocytic leukemic B-cells but not normal B-cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998; 91: 2387–2396.

    PubMed  CAS  Google Scholar 

  49. Biondi A, Rossi V, Bassan R, et al. Constitutive expression of the interleukin-6 gene in chronic lymphocytic leukemia. Blood 1989; 73: 1279–1284.

    PubMed  CAS  Google Scholar 

  50. Fayad L, Keating MJ, Reuben JM, et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001; 97: 256–263.

    Article  PubMed  CAS  Google Scholar 

  51. Hulkkonen J, Vilpo J, Vilpo L, Hurme M. Diminished production of interleukin-6 in chronic lymphocytic leukaemia (B-CLL) cells from patients at advanced stages of disease. Tampere CLL Group. Br J Haematol 1998; 100: 478–483.

    Article  PubMed  CAS  Google Scholar 

  52. Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 1989; 84: 1045–1049.

    Article  PubMed  CAS  Google Scholar 

  53. Mukaida N. Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation. Int J Hematol 2000; 72: 391–398.

    PubMed  CAS  Google Scholar 

  54. Hermouet S, Corre I, Lippert E. Interleukin-8 and other agonists of Gi2 proteins: autocrine paracrine growth factors for human hematopoietic progenitors acting in synergy with colony stimulating factors. Leuk Lymphoma 2000; 38: 39–48.

    PubMed  CAS  Google Scholar 

  55. Srivastava MD, Srivastava R, Srivastava BI. Constitutive production of interleukin-8 (IL-8) by normal and malignant human B-cells and other cell types. Leuk Res 1993; 17: 1063–1069.

    Article  PubMed  CAS  Google Scholar 

  56. Francia di Celle P, Carbone A, Marchis D, et al. Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein. Blood 1994; 84: 220–228.

    Google Scholar 

  57. Francia di Celle P, Mariani S, Riera L, Stacchini A, Reato G, Foa R. Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. Blood 1996; 87: 4382–4389.

    Google Scholar 

  58. Molica S, Vitelli G, Levato D, Levato L, Dattilo A, Gandolfo GM. Clinico-biological implications of increased serum levels of interleukin-8 in B-cell chronic lymphocytic leukemia. Haematologica 1999; 84: 208–211.

    PubMed  CAS  Google Scholar 

  59. Stratowa C, Loffler G, Lichter P, et al. cDNA microarray gene expression analysis of B-cell chronic lymphocytic leukemia proposes potential new prognostic markers involved in lymphocyte trafficking. Int J Cancer 2001; 91: 474–480.

    Article  PubMed  CAS  Google Scholar 

  60. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991; 147: 3815–3822.

    PubMed  CAS  Google Scholar 

  61. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Thl) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150: 353–360.

    PubMed  Google Scholar 

  62. Mosmann TR, Moore KW. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today 1991; 12: A49–53.

    Article  PubMed  CAS  Google Scholar 

  63. Levy Y, Brouet JC. Interleukin-10 prevents spontaneous death of germinal center B-cells by induction of the bc1–2 protein. J Clin Invest 1994; 93: 424–428.

    Article  PubMed  CAS  Google Scholar 

  64. Finke J, Ternes P, Lange W, Mertelsmann R, Dolken G. Expression of interleukin 10 in B-lymphocytes of different origin. Leukemia 1993; 7: 1852–1857.

    PubMed  CAS  Google Scholar 

  65. Sjoberg J, Aguilar-Santelises M, Sjogren AM, et al. Interleukin-10 mRNA expression in B-cell chronic lymphocytic leukaemia inversely correlates with progression of disease. Br J Haematol 1996; 92: 393–400.

    Article  PubMed  CAS  Google Scholar 

  66. Tangye SG, Weston KM, Raison RL. Interleukin-10 inhibits the in vitro proliferation of human activated leukemic CD5+ B-cells. Leuk Lymphoma 1998; 31: 121–130.

    Article  PubMed  CAS  Google Scholar 

  67. Fluckiger AC, Durand I, Banchereau J. Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells. J Exp Med 1994; 179: 91–99.

    Article  PubMed  CAS  Google Scholar 

  68. Castejon R, Vargas JA, Romero Y, Briz M, Munoz RM, Durantez A. Modulation of apoptosis by cytokines in B-cell chronic lymphocytic leukemia. Cytometry 1999; 38: 224–230.

    Article  PubMed  CAS  Google Scholar 

  69. Kitabayashi A, Hirokawa M, Miura AB. The role of interleukin-10 (IL-10) in chronic B-lymphocytic leukemia: IL-10 prevents leukemic cells from apoptotic cell death. Int J Hematol 1995; 62: 99–106.

    Article  PubMed  CAS  Google Scholar 

  70. Jurlander J, Lai CF, Tan J, et al. Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells. Blood 1997; 89: 4146–4152.

    PubMed  CAS  Google Scholar 

  71. Peng B, Zhang M, Sun R, et al. The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL). Leuk Res 1998; 22: 509–516.

    Article  PubMed  CAS  Google Scholar 

  72. Yen Chong S, Lin YC, et al. Cell cycle effects of IL-10 on malignant B-1 cells. Genes Immun 2001; 2: 239–247.

    Article  Google Scholar 

  73. Egle A, Marschitz I, Posch B, Herold M, Greil R. IL-10 serum levels in B-cell chronic lymphocytic leukaemia. Br J Haematol 1996; 94: 211–212.

    PubMed  CAS  Google Scholar 

  74. Kamper EF, Papaphilis AD, Angelopoulou MK, et al. Serum levels of tetranectin, intercellular adhesion molecule-1 and interleukin-10 in B-chronic lymphocytic leukemia. Clin Biochem 1999; 32: 639–645.

    Article  PubMed  CAS  Google Scholar 

  75. Brenner MK. Tumour necrosis factor. Br J Haematol 1988; 69: 149–152.

    Article  PubMed  CAS  Google Scholar 

  76. Gehr G, Gentz R, Brockhaus M, Loetscher H, Lesslauer W. Both tumor necrosis factor receptor types mediate proliferative signals in human mononuclear cell activation. J Immunol 1992; 149: 911–917.

    PubMed  CAS  Google Scholar 

  77. Cordingley FT, Bianchi A, Hoffbrand AV, et al. Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies. Lancet 1988; 1: 969–971.

    Article  PubMed  CAS  Google Scholar 

  78. Foa R, Massaia M, Cardona S, et al. Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. Blood 1990; 76: 393–400.

    PubMed  CAS  Google Scholar 

  79. Trentin L, Zambello R, Agostini C, et al. Expression and regulation of tumor necrosis factor, interleukin-2, and hematopoietic growth factor receptors in B-cell chronic lymphocytic leukemia. Blood 1994; 84: 4249–4256.

    PubMed  CAS  Google Scholar 

  80. Waage A, Espevik T. TNF receptors in chronic lymphocytic leukemia. Leuk Lymphoma 1994; 13: 41–46.

    Article  PubMed  CAS  Google Scholar 

  81. Adami F, Guarini A, Pini M, et al. Serum levels of tumour necrosis factor-alpha in patients with B-cell chronic lymphocytic leukaemia. Eur J Cancer 1994; 30A: 1259–1263.

    Article  Google Scholar 

  82. Aguilar-Santelises M, Gigliotti D, Osorio LM, Santiago AD, Mellstedt H, Jondal M. Cytokine expression in BCLL in relation to disease progression and in vitro activation. Med Oncol 1999; 16: 289–295.

    Article  PubMed  CAS  Google Scholar 

  83. Digel W, Stefanic M, Schoniger W, et al. Tumor necrosis factor induces proliferation of neoplastic B-cells from chronic lymphocytic leukemia. Blood 1989; 73: 1242–1246.

    PubMed  CAS  Google Scholar 

  84. Burke F, Griffin D, Elwood N, et al. The effect of cytokines on cultured mononuclear cells from patients with B cell chronic lymphocytic leukemia. Hematol Oncol 1993; 11: 23–33.

    Article  PubMed  CAS  Google Scholar 

  85. Heslop HE, Bianchi AC, Cordingley FT, et al. Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders. J Exp Med 1990; 172: 1729–1734.

    Article  PubMed  CAS  Google Scholar 

  86. Sivaraman S, Deshpande CG, Ranganathan R, et al. Tumor necrosis factor modulates CD20 expression on cells from chronic lymphocytic leukemia: a new role for TNF alpha? Microsc Res Tech 2000; 50: 251–257.

    Article  PubMed  CAS  Google Scholar 

  87. Venugopal P, Sivaraman S, Huang XK, Nayini J, Gregory SA, Preisler HD. Effects of cytokines on CD20 antigen expression on tumor cells from patients with chronic lymphocytic leukemia. Leuk Res 2000; 24: 411–415.

    Article  PubMed  CAS  Google Scholar 

  88. Rubin BY, Gupta SL. Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc Natl Acad Sci USA 1980; 77: 5928–5932.

    Article  PubMed  CAS  Google Scholar 

  89. Nakamura M, Manser T, Pearson GD, Daley MJ, Gefter ML. Effect of IFN-gamma on the immune response in vivo and on gene expression in vitro. Nature 1984; 307: 381–382.

    Article  PubMed  CAS  Google Scholar 

  90. Sen GC, Lengyel P. The interferon system. A bird’s eye view of its biochemistry. J Biol Chem 1992; 267: 50175020.

    Google Scholar 

  91. Goldstein D, Laszlo J. Interferon therapy in cancer: from imaginon to interferon. Cancer Res 1986; 46: 43154329.

    Google Scholar 

  92. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330: 820–825.

    Article  Google Scholar 

  93. Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med 1993; 177: 213–218.

    Article  PubMed  CAS  Google Scholar 

  94. Rojas R, Roman J, Torres A, et al. Inhibition of apoptotic cell death in B-CLL by interferon gamma correlates with clinical stage. Leukemia 1996; 10: 1782–1788.

    PubMed  CAS  Google Scholar 

  95. Zaki M, Douglas R, Patten N, Bachinsky M, Lamb R, Nowell P, Moore J. Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B-cells to apoptosis. Leuk Res 2000; 24: 611–621.

    Article  PubMed  CAS  Google Scholar 

  96. Mainou-Fowler T, Prentice AG. Modulation of apoptosis with cytokines in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma 1996; 21: 369–377.

    Article  PubMed  CAS  Google Scholar 

  97. Panayiotidis P, Ganeshaguru K, Jabbar SA, Hoffbrand AV. Alpha-interferon (alpha-IFN) protects B-chronic lymphocytic leukaemia cells from apoptotic cell death in vitro. Br J Haematol 1994; 86: 169–173.

    Article  PubMed  CAS  Google Scholar 

  98. Jewell AP, Worman CP, Lydyard PM, Yong KL, Giles FJ, Goldstone AH. Interferon-alpha up-regulates bcl2 expression and protects B-CLL cells from apoptosis in vitro and in vivo. Br J Haematol 1994; 88: 268–274.

    Article  PubMed  CAS  Google Scholar 

  99. Chaouchi N, Wallon C, Taieb J, et al. Interferon-alpha-mediated prevention of in vitro apoptosis of chronic lymphocytic leukemia B-cells: role of bcl-2 and c-myc. Clin Immunol Immunopathol 1994; 73: 197–204.

    Article  PubMed  CAS  Google Scholar 

  100. McSweeney EN, Giles FJ, Worman CP, et al. Recombinant interferon alfa 2a in the treatment of patients with early stage B chronic lymphocytic leukaemia. Br J Haematol 1993; 85: 77–83.

    Article  PubMed  CAS  Google Scholar 

  101. Heslop HE, Brenner MK, Ganeshaguru K, Hoffbrand AV. Possible mechanism of action of interferon alpha in chronic B-cell malignancies. Br J Haematol 1991; 79 (suppl 1): 14–16.

    Article  PubMed  Google Scholar 

  102. Jewell AP. Interferon-alpha, Bcl-2 expression and apoptosis in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1996; 21: 43–47.

    Article  PubMed  CAS  Google Scholar 

  103. Ostlund L, Einhorn S, Robert KH, Juliusson G, Biberfeld P. Chronic B-lymphocytic leukemia cells proliferate and differentiate following exposure to interferon in vitro. Blood 1986; 67: 152–159.

    PubMed  CAS  Google Scholar 

  104. Totterman TH, Carlsson M, Nilsson K. Induction of IgM secretion by chronic B-lymphocytic leukaemia cells in serum-free medium: effects of interferon-alpha, -gamma and phorbol ester. Clin Exp Immunol 1988; 71: 187–192.

    PubMed  CAS  Google Scholar 

  105. Jewell AP, Yong KL, Worman CP, Giles FT, Goldstone AH, Lydyard PM. Cytokine induction of leucocyte adhesion molecule-1 (LAM-1) expression on chronic lymphocytic leukaemia cells. Leukemia 1992; 6: 400–104.

    PubMed  CAS  Google Scholar 

  106. Csanaky G, Vass JA, Losonczy H, Schmelczer M. Expression of an adhesion molecule and homing in B-cell chronic lymphocytic leukaemia: II. L-selectin expression mediated cell adhesion revealed by immobilized analogue carbohydrates in B-cell chronic lymphocytic leukaemia and monoclonal lymphocytosis of undetermined significance. Med Oncol Tumor Pharmacother 1993; 10: 173–180.

    PubMed  CAS  Google Scholar 

  107. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med 1992; 327: 28–35.

    Article  PubMed  CAS  Google Scholar 

  108. Khwaja A, Linch DC. Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on neutrophil formation and function. Curr Opin Hematol 1994; 1: 216–220.

    PubMed  CAS  Google Scholar 

  109. Nishijima I, Nakahata T, Hirabayashi Y, et al. A human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitors to all lineages in response to human GM-CSF. Mol Biol Cell 1995; 6: 497–508.

    PubMed  CAS  Google Scholar 

  110. Ni K, O’Neill HC. Proliferation of the BCL1 B cell lymphoma induced by IL-4 and IL-5 is dependent on IL-6 and GM-CSF. Immunol Cell Biol 1992; 70: 315–322.

    Article  PubMed  CAS  Google Scholar 

  111. Till KJ, Burthem J, Lopez A, Cawley JC. Granulocyte-macrophage colony-stimulating factor receptor: stage-specific expression and function on late B-cells. Blood 1996; 88: 479–486.

    PubMed  CAS  Google Scholar 

  112. Zupo S, Perussia B, Baldi L, et al. Production of granulocyte-macrophage colony-stimulating factor but not IL-3 by normal and neoplastic human B-lymphocytes. J Immunol 1992; 148: 1423–1430.

    PubMed  CAS  Google Scholar 

  113. Harris RJ, Pettitt AR, Schmutz C, et al. Granuloctye-macrophage colony-stimulating factor as an autocrine survival factor for mature normal and malignant B-lymphocytes. J Immunol 2000; 164: 3887–3893.

    PubMed  CAS  Google Scholar 

  114. Corcione A, Corrias MV, Daniele S, Zupo S, Spriano M, Pistoia V. Expression of granulocyte colony-stimulating factor and granulocyte colony-stimulating factor receptor genes in partially overlapping monoclonal B-cell populations from chronic lymphocytic leukemia patients. Blood 1996; 87: 2861–2869.

    PubMed  CAS  Google Scholar 

  115. Corcione A, Pistoia V. B-cell-derived granulocyte-colony stimulating factor (G-CSF). Methods 1997; 11: 143–147.

    Article  PubMed  CAS  Google Scholar 

  116. Handa A, Kashimura T, Takeuchi S, et al. Expression of functional granulocyte colony-stimulating factor receptors on human B-lymphocytic leukemia cells. Ann Hematol 2000; 79: 127–131.

    Article  PubMed  CAS  Google Scholar 

  117. Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 1988; 167: 219–224.

    Article  PubMed  CAS  Google Scholar 

  118. Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood 1992; 79: 3101–3109.

    PubMed  CAS  Google Scholar 

  119. Hayes TG, Tan XL, Moseley AB, Huston MM, Huston DP. Abnormal response to IL-5 in B-cell chronic lymphocytic leukemia. Leuk Res 1993; 17: 777–783.

    Article  PubMed  CAS  Google Scholar 

  120. Carlsson M, Totterman TH, Rosen A, Nilsson K. Interleukin-2 and a T cell hybridoma (MP6) derived B cell-stimulatory factor act synergistically to induce proliferation and differentiation of human B-chronic lymphocytic leukemia cells. Leukemia 1989; 3: 593–601.

    PubMed  CAS  Google Scholar 

  121. Tavernier J, Devos R, Van der Heyden J, et al. Expression of human and murine interleukin-5 in eukaryotic systems. DNA 1989; 8: 491–501.

    Article  PubMed  CAS  Google Scholar 

  122. Mainou-Fowler T, Craig VA, Copplestone JA, Hamon MD, Prentice AG. Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bc1–2 expression and is inhibited by IL-4. Blood 1994; 84: 2297–2304.

    PubMed  CAS  Google Scholar 

  123. Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990; 6: 597–641.

    Article  PubMed  CAS  Google Scholar 

  124. Wallick SC, Figari IS, Morris RE, Levinson AD, Palladino MA. Immunoregulatory role of transforming growth factor beta (TGF-beta) in development of killer cells: comparison of active and latent TGF-beta 1. J Exp Med 1990; 172: 1777–1784.

    Article  PubMed  CAS  Google Scholar 

  125. Kremer JP, Reisbach G, Nerl C, Dormer P. B-cell chronic lymphocytic leukaemia cells express and release transforming growth factor-beta. Br J Haematol 1992; 80: 480–487.

    Article  PubMed  CAS  Google Scholar 

  126. Schena M, Gaidano G, Gottardi D, et al. Molecular investigation of the cytokines produced by normal and malignant B-lymphocytes. Leukemia 1992; 6: 120–125.

    PubMed  CAS  Google Scholar 

  127. Lotz M, Ranheim E, Kipps TJ. Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B-cells. J Exp Med 1994; 179: 999–1004.

    Article  PubMed  CAS  Google Scholar 

  128. Israels LG, Israels SJ, Begleiter A, et al. Role of transforming growth factor-beta in chronic lymphocytic leukemia. Leuk Res 1993; 17: 81–87.

    Article  PubMed  CAS  Google Scholar 

  129. DeCoteau JF, Knaus PI, Yankelev H, et al. Loss of functional cell surface transforming growth factor beta (TGFbeta) type l receptor correlates with insensitivity to TGF-beta in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1997; 94: 5877–5881.

    Article  PubMed  CAS  Google Scholar 

  130. Lagneaux L, Delforge A, Bron D, Massy M, Bernier M, Stryckmans P. Heterogenous response of B-lymphocytes to transforming growth factor-beta in B-cell chronic lymphocytic leukaemia: correlation with the expression of TGF-beta receptors. Br J Haematol 1997; 97: 612–620.

    Article  PubMed  CAS  Google Scholar 

  131. Douglas RS, Capocasale RJ, Lamb RJ, Nowell PC, Moore JS. Chronic lymphocytic leukemia B-cells are resistant to the apoptotic effects of transforming growth factor-beta. Blood 1997; 89: 941–947.

    PubMed  CAS  Google Scholar 

  132. Lagneaux L, Delforge A, Bernier M, Stryckmans P, Bron D. TGF-beta activity and expression of its receptors in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1998; 31: 99–106.

    Article  PubMed  CAS  Google Scholar 

  133. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.

    Article  PubMed  CAS  Google Scholar 

  134. Ellis LM, Fidler U. Angiogenesis and metastasis. Eur J Cancer 1996; 32A: 2451–2460.

    Article  Google Scholar 

  135. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997; 150: 815–821.

    PubMed  CAS  Google Scholar 

  136. Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000; 95: 309–313.

    PubMed  CAS  Google Scholar 

  137. Fiedler W, Graeven U, Ergun S, et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 1997; 89: 1870–1875.

    PubMed  CAS  Google Scholar 

  138. Kini AR, Kay NE, Peterson LC. Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia 2000; 14: 1414–1418.

    Article  PubMed  CAS  Google Scholar 

  139. Chen H, Treweeke AT, West DC, et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood 2000; 96: 3181–3187.

    PubMed  CAS  Google Scholar 

  140. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–1309.

    Article  PubMed  CAS  Google Scholar 

  141. Thomas KA. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem 1996; 271: 603–606.

    Article  PubMed  CAS  Google Scholar 

  142. Molica S, Vitelli G, Levato D, Gandolfo GM, Liso V. Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 107: 605–610.

    Article  PubMed  CAS  Google Scholar 

  143. Aguayo A, O’Brien S, Keating M, et al. Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia. Blood 2000; 96: 768–770.

    PubMed  CAS  Google Scholar 

  144. Aguayo A, Manshouri T, O’Brien S, et al. Clinical relevance of Fitt and Tiel angiogenesis receptors expression in B-cell chronic lymphocytic leukemia (CLL). Leuk Res 2001; 25: 279–285.

    Article  PubMed  CAS  Google Scholar 

  145. Ferrajoli A, Manshouri T, Estrov Z, et al. High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia. Clin Cancer Res 2001; 7: 795–799.

    PubMed  CAS  Google Scholar 

  146. Griffin JD, Rambaldi A, Vellenga E, Young DC, Ostapovicz D, Cannistra SA. Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors. Blood 1987; 70: 1218–1221.

    PubMed  CAS  Google Scholar 

  147. Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999; 59: 728–733.

    PubMed  CAS  Google Scholar 

  148. Han T, Barcos M, Emrich L, et al. Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data J Clin Oncol 1984; 2: 562–570.

    CAS  Google Scholar 

  149. Pangalis GA, Roussou PA, Kittas C, et al. Patterns of bone marrow involvement in chronic lymphocytic leukemia and small lymphocytic (well differentiated) non-Hodgkin’s lymphoma. Its clinical significance in relation to their differential diagnosis and prognosis. Cancer 1984; 54: 702–708.

    Article  PubMed  CAS  Google Scholar 

  150. Rollins BJ. Chemokines. Blood 1997; 90: 909–928.

    PubMed  CAS  Google Scholar 

  151. Mackay CR. Chemokines: immunology’s high impact factors. Nat Immunol 2001; 2: 95–101.

    Article  PubMed  CAS  Google Scholar 

  152. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; 392: 565–568.

    Article  PubMed  CAS  Google Scholar 

  153. Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol 2001; 2: 123–128.

    Article  PubMed  CAS  Google Scholar 

  154. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.

    Article  PubMed  CAS  Google Scholar 

  155. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.

    Article  PubMed  CAS  Google Scholar 

  156. Kawabata K, Ujikawa M, Egawa T, et al. A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc Natl Acad Sci USA 1999; 96: 5663–5667.

    Article  PubMed  CAS  Google Scholar 

  157. Nishii K, Katayama N, Miwa H, et al. Survival of human leukaemic B-cell precursors is supported by stromal cells and cytokines: association with the expression of bc1–2 protein. Br J Haematol 1999; 105: 701–710.

    Article  PubMed  CAS  Google Scholar 

  158. Bleui CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 1996; 184: 1101–1109.

    Article  Google Scholar 

  159. Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10: 463–471.

    Article  PubMed  CAS  Google Scholar 

  160. Mohle R, Failenschmid C, Bautz F, Kanz L. Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia 1999; 13: 1954–1959.

    Article  PubMed  CAS  Google Scholar 

  161. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B-cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 1999; 94: 3658–3667.

    PubMed  CAS  Google Scholar 

  162. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell’Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B-cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 2000; 96: 2655–2663.

    PubMed  CAS  Google Scholar 

  163. Loetscher M, Gerber B, Loetscher P, et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 1996; 184: 963–969.

    Article  PubMed  CAS  Google Scholar 

  164. Piali L, Weber C, LaRosa G, et al. The chemokine receptor CXCR3 mediates rapid and shear-resistant adhesion-induction of effector T-lymphocytes by the chemokines IP10 and Mig. Eur J Immunol 1998; 28: 961–972.

    Article  PubMed  CAS  Google Scholar 

  165. Trentin L, Agostini C, Facco M, et al. The chemokine receptor CXCR3 is expressed on malignant B-cells and mediates chemotaxis. J Clin Invest 1999; 104: 115–121.

    Article  PubMed  CAS  Google Scholar 

  166. Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM. The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. Blood 2000; 95: 627–632.

    PubMed  CAS  Google Scholar 

  167. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121–127.

    Article  PubMed  CAS  Google Scholar 

  168. Till KJ, Zuzel M, Cawley JC. The role of hyaluronan and interleukin 8 in the migration of chronic lymphocytic leukemia cells within lymphoreticular tissues. Cancer Res 1999; 59: 4419–4426.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Enrica Orsini MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin Foa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Section of Hematology/Oncology, Veterans Affairs Medical Center, Augusta, GA, USA

    Guy B. Faguet MD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Orsini, E., Foa, R. (2004). Cytokines and Soluble Molecules in CLL. In: Faguet, G.B. (eds) Chronic Lymphocytic Leukemia. Contemporary Hematology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-412-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-412-2_6

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-355-8

  • Online ISBN: 978-1-59259-412-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation