Current Hematologic Malignancy Reports

, Volume 7, Issue 1, pp 26–33 | Cite as

Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (S O’Brien, Section Editor)

Abstract

B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), or phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to “mobilization” of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.

Keywords

Chronic lymphocytic leukemia CLL Signaling pathways Syk Btk PI3K delta B-cell receptor BCR Chemokine receptors CXCR4 CXCR5 Microenvironment Kinase inhibitors B lymphocytes ZAP-70 Fostamatinib PCI-32765 CAL-101 Therapy 

Notes

Acknowledgments

This manuscript was supported by a CLL Global Research Foundation grant and a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to J.A.B.).

Disclosure

Conflicts of Interest: J. Burger: Research funding grants (in addition to those mentioned above) from Calistoga, Genzyme, Gilead, and Pharmacyclics; consulting fees from Genzyme, Noxxon, and Pharmacyclics.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114(16):3367–75.PubMedCrossRefGoogle Scholar
  3. 3.
    Stein H, Bonk A, Tolksdorf G, Lennert K, Rodt H, Gerdes J. Immunohistologic analysis of the organization of normal lymphoid tissue and non-Hodgkin’s lymphomas. J Histochem Cytochem. 1980;28(8):746–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood. 2008;111(10):5173–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. The Journal of Clinical Investigation. 2005;115(3):755–64.PubMedGoogle Scholar
  6. 6.
    Burkle A, Niedermeier M, Schmitt-Graff A, Wierda WG, Keating MJ, Burger JA. Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood. 2007;110(9):3316–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Bhattacharya N, Diener S, Idler IS, Barth TF, Rauen J, Habermann A, et al. Non-malignant B cells and chronic lymphocytic leukemia cells induce a pro-survival phenotype in CD14+ cells from peripheral blood. Leukemia. 2011;25(4):722–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Ruan J, Hyjek E, Kermani P, Christos PJ, Hooper AT, Coleman M, et al. Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin’s lymphoma. Clin Cancer Res. 2006;12(19):5622–31.PubMedCrossRefGoogle Scholar
  9. 9.
    Ghia P, Strola G, Granziero L, Geuna M, Guida G, Sallusto F, et al. Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. Eur J Immunol. 2002;32(5):1403–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Ghia P, Caligaris-Cappio F. The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms. Adv Cancer Res. 2000;79:157–73.PubMedCrossRefGoogle Scholar
  11. 11.
    •• Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011;117(2):563–574. This study provides the first direct evidence for BCR activation in CLL in the lymphatic tissues. PubMedCrossRefGoogle Scholar
  12. 12.
    Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood. 2004;103(12):4389–95.PubMedCrossRefGoogle Scholar
  13. 13.
    • Burger JA, Quiroga MP, Hartmann E, Burkle A, Wierda WG, Keating MJ, et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood 2009; 13(13):3050–8. This paper characterizes CCL3 gene upregulation in CLL cells as response to the microenvironment, particularly after BCR activation. PubMedCrossRefGoogle Scholar
  14. 14.
    Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2002;100(13):4609–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200(4):519–25.PubMedCrossRefGoogle Scholar
  17. 17.
    Widhopf 2nd GF, Rassenti LZ, Toy TL, Gribben JG, Wierda WG, Kipps TJ. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood. 2004;104(8):2499–504.PubMedCrossRefGoogle Scholar
  18. 18.
    Chiorazzi N, Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol. 2003;21:841–94.PubMedCrossRefGoogle Scholar
  19. 19.
    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Pighi C, Gu TL, Dalai I, Barbi S, Parolini C, Bertolaso A, et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34(2):141–53.Google Scholar
  21. 21.
    Rinaldi A, Kwee I, Taborelli M, Largo C, Uccella S, Martin V, et al. Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br J Haematol. 2006;132(3):303–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Cecconi D, Zamo A, Bianchi E, Parisi A, Barbi S, Milli A, et al. Signal transduction pathways of mantle cell lymphoma: a phosphoproteome-based study. Proteomics. 2008;8(21):4495–506.PubMedCrossRefGoogle Scholar
  23. 23.
    Martinez N, Camacho FI, Algara P, Rodriguez A, Dopazo A, Ruiz-Ballesteros E, et al. The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res. 2003;63(23):8226–32.PubMedGoogle Scholar
  24. 24.
    Rizzatti EG, Falcao RP, Panepucci RA, Proto-Siqueira R, Anselmo-Lima WT, Okamoto OK, et al. Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways. Br J Haematol. 2005;130(4):516–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319(5870):1676–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296(5573):1641–2.PubMedCrossRefGoogle Scholar
  27. 27.
    Wang LD, Clark MR. B-cell antigen-receptor signalling in lymphocyte development. Immunology. 2003;110(4):411–20.PubMedCrossRefGoogle Scholar
  28. 28.
    Reth M. Antigen receptors on B lymphocytes. Annu Rev Immunol. 1992;10:97–121.PubMedCrossRefGoogle Scholar
  29. 29.
    Liu W, Meckel T, Tolar P, Sohn HW, Pierce SK. Intrinsic properties of immunoglobulin IgG1 isotype-switched B cell receptors promote microclustering and the initiation of signaling. Immunity. 2010;32(6):778–89.PubMedCrossRefGoogle Scholar
  30. 30.
    Bernal A, Pastore RD, Asgary Z, Keller SA, Cesarman E, Liou HC, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood. 2001;98(10):3050–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2008;111(2):846–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP, et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature. 1995;378(6554):298–302.PubMedCrossRefGoogle Scholar
  33. 33.
    Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T. Syk tyrosine kinase required for mouse viability and B-cell development. Nature. 1995;378(6554):303–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Young RM, Hardy IR, Clarke RL, Lundy N, Pine P, Turner BC, et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood. 2009;113(11):2508–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Zarbock A, Lowell CA, Ley K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1. Immunity. 2007;26(6):773–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE. Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk. J Biol Chem. 2000;275(23):17263–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH, Medrano-Ramirez G, Morales-Torres JL, et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58(11):3309–18.PubMedCrossRefGoogle Scholar
  38. 38.
    Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006;319(3):998–1008.PubMedCrossRefGoogle Scholar
  39. 39.
    • Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al: Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115(13):2578–85. This is the first report about the clinical activity of an inhibitor of a BCR-associated kinase, Syk. PubMedCrossRefGoogle Scholar
  40. 40.
    Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of Bruton’s tyrosine kinase protein within the B cell lineage. European journal of immunology. 1994;24(12):3100–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol. 2009;27:199–227.PubMedCrossRefGoogle Scholar
  43. 43.
    Petro JB, Rahman SM, Ballard DW, Khan WN. Bruton’s tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med. 2000;191(10):1745–54.PubMedCrossRefGoogle Scholar
  44. 44.
    Spaargaren M, Beuling EA, Rurup ML, Meijer HP, Klok MD, Middendorp S, et al. The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med. 2003;198(10):1539–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Ortolano S, Hwang IY, Han SB, Kehrl JH. Roles for phosphoinositide 3-kinases, Bruton’s tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing. Eur J Immunol. 2006;36(5):1285–95.PubMedCrossRefGoogle Scholar
  46. 46.
    de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26(1):93–104.PubMedCrossRefGoogle Scholar
  47. 47.
    •• Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al: The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107(29):13075–80. This article presents a characterization of the first-in-man Btk inhibitor. PubMedCrossRefGoogle Scholar
  48. 48.
    Burger JA, O’Brien S, Fowler N, Advani R, Sharman JP, Furman RR, et al. The Bruton’s tyrosine kinase inhibitor, PCI-32765, is well tolerated and demonstrates promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): an update on ongoing phase 1 studies [abstract]. Blood. 2010;116(21):32a.Google Scholar
  49. 49.
    Advani R, Sharman JP, Smith SM, Pollyea DA, Boyd TE, Grant BW, et al. Effect of Btk inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL: evidence of antitumor activity from a phase I study [abstract]. J Clin Oncol. 2010;2010:8012a.Google Scholar
  50. 50.
    Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287–96.PubMedCrossRefGoogle Scholar
  51. 51.
    Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009;139(3):573–86.PubMedCrossRefGoogle Scholar
  52. 52.
    Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317–30.PubMedCrossRefGoogle Scholar
  53. 53.
    Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22(24):8580–91.PubMedCrossRefGoogle Scholar
  54. 54.
    Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002;196(6):753–63.PubMedCrossRefGoogle Scholar
  55. 55.
    Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583):1031–4.PubMedGoogle Scholar
  56. 56.
    Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C, et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood. 2002;100(10):3741–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Kienle D, Benner A, Krober A, Winkler D, Mertens D, Buhler A, et al. Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes. Blood. 2006;107(5):2090–3.PubMedCrossRefGoogle Scholar
  58. 58.
    Edelmann J, Klein-Hitpass L, Carpinteiro A, Fuhrer A, Sellmann L, Stilgenbauer S, et al. Bone marrow fibroblasts induce expression of PI3K/NF-kappaB pathway genes and a pro-angiogenic phenotype in CLL cells. Leuk Res. 2008;32(10):1565–72.PubMedCrossRefGoogle Scholar
  59. 59.
    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(11):3658–67.PubMedGoogle Scholar
  60. 60.
    Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110{delta} selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078–88.PubMedCrossRefGoogle Scholar
  62. 62.
    Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, et al. PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 116(9):1460–8.Google Scholar
  63. 63.
    Furman RR, Byrd JC, Brown JR, Coutre SE, Benson Jr DM, Wagner-Johnston ND, et al. CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia [abstract]. Blood. 2010;116(21):31a.Google Scholar
  64. 64.
    • Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603–12. These in vitro and correlative data explain the clinical activity of the PI3K delta inhibitor CAL-101. PubMedCrossRefGoogle Scholar
  65. 65.
    Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood. 2005;105(5):2036–41.PubMedCrossRefGoogle Scholar
  66. 66.
    Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009;114(5):1029–37.PubMedCrossRefGoogle Scholar
  67. 67.
    • Sivina M, Hartmann E, Kipps TJ, Rassenti L, Krupnik D, Lerner S, et al. CCL3 (MIP-1alpha) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood 2011;117(5):1662–9. This paper describes CCL3 as a BCR-related new prognostic marker in CLL. PubMedCrossRefGoogle Scholar
  68. 68.
    Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992;71(4):649–62.PubMedCrossRefGoogle Scholar
  69. 69.
    Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101(12):4944–51.PubMedCrossRefGoogle Scholar
  70. 70.
    Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348(18):1764–75.PubMedCrossRefGoogle Scholar
  71. 71.
    Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351(9):893–901.PubMedCrossRefGoogle Scholar
  72. 72.
    Chen L, Huynh L, Apgar J, Tang L, Rassenti L, Weiss A, et al. ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia. Blood. 2008;111(5):2685–92.PubMedCrossRefGoogle Scholar
  73. 73.
    Richardson SJ, Matthews C, Catherwood MA, Alexander HD, Carey BS, Farrugia J, et al. ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006;107(9):3584–92.PubMedCrossRefGoogle Scholar
  74. 74.
    Messmer D, Fecteau JF, O’Hayre M, Bharati IS, Handel TM, Kipps TJ. Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib. Blood. 2011;117(3):882–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Schall TJ, Bacon K, Camp RD, Kaspari JW, Goeddel DV. Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. J Exp Med. 1993;177(6):1821–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Krzysiek R, Lefevre EA, Zou W, Foussat A, Bernard J, Portier A, et al. Antigen receptor engagement selectively induces macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta chemokine production in human B cells. J Immunol. 1999;162(8):4455–63.PubMedGoogle Scholar
  77. 77.
    Eberlein J, Nguyen TT, Victorino F, Golden-Mason L, Rosen HR, Homann D. Comprehensive assessment of chemokine expression profiles by flow cytometry. J Clin Invest. 2010;120(3):907–23.PubMedCrossRefGoogle Scholar
  78. 78.
    Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity. 2000;13(2):199–212.PubMedCrossRefGoogle Scholar
  79. 79.
    Zucchetto A, Benedetti D, Tripodo C, Bomben R, Dal Bo M, Marconi D, et al. CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer Res. 2009;69(9):4001–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Palacios F, Moreno P, Morande P, Abreu C, Correa A, Porro V, et al. High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease. Blood. 2010;115(22):4488–96.PubMedCrossRefGoogle Scholar
  81. 81.
    Hamed H, Zaki S. Role of CCL3 protein (monocyte inflammatory protein-1 alpha) in lymphoid malignancy. Egypt J Immunol. 2007;14(1):63–72.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Leukemia, Unit 428The University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations