B-Cell Receptor Signaling Pathway: Mechanisms and Inhibitors

E.A. Nikitin,

DOI:

https://doi.org/10.21320/2500-2139-2014-7-3-251-263

Differentiation and survival of normal B-lymphocytes critically depends on the B-cell receptor (BCR) signaling pathway. Lymphoid malignancies use different aspects of the BCR-signaling pathway to provide their proliferation and growth. They manifest themselves in different forms, such as the form of BCR particular antigenic specificity, or the form of activating or, to the contrary, inhibiting gene mutations encoding proteins involved in BCR-signaling. A number of small molecules inhibit different proteins of BCR-signaling cascade. In this review, we dwell on normal and defective BCR-signaling pathways, as well as on tyrosine kinase inhibitors that are being widely used in clinical trials and will likely change the management of lymphoid malignancies.

  • E.A. Nikitin Hematology Research Center, RF MH, Moscow, Russian Federation ; ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация
  1. Dameshek W., Schwartz R.S. Leukemia and auto-immunization-some possible relationships. Blood 1959; 14: 1151–8. DOI: https://doi.org/10.1182/blood.V14.10.1151.1151
  2. Goodlad J.R. et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am. J. Surg. Pathol. 2000; 24(9): 1279–85. DOI: https://doi.org/10.1097/00000478-200009000-00012
  3. Vasudevan B., Chatterjee M. Lyme borreliosis and skin. Indian J. Dermatol. 2013; 58(3): 167–74. DOI: https://doi.org/10.4103/0019-5154.110822
  4. Schollkopf C., Melbye M., Munksgaard L. et al. Borrelia infection and risk of non-Hodgkin lymphoma. Blood 2008; 111(12): 5524–9. DOI: https://doi.org/10.1182/blood-2007-08-109611
  5. Garbe C., Stein H., Dienemann D., Orfanos C.E. Borrelia burgdorferiassociated cutaneous B cell lymphoma: clinical and immunohistologic characterization of four cases. J. Am. Acad. Dermatol. 1991; 24(4): 584–90. DOI: https://doi.org/10.1016/0190-9622(91)70088-J
  6. Wotherspoon A.C., Doglioni C., Diss T.C. et al. Regression of primary lowgrade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342(8871): 575–7. DOI: https://doi.org/10.1016/0140-6736(93)91409-F
  7. Du M.Q., Isaccson P.G. Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol. 2002; 3(2): 97–104. DOI: https://doi.org/10.1016/S1470-2045(02)00651-4
  8. Ferreri A.J., Ponzoni M., Guidoboni M. et al. Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy. J. Clin. Oncol. 2005; 23(22): 5067–73. DOI: https://doi.org/10.1200/JCO.2005.07.083
  9. Ferreri A.J., Govi S., Pasini E. et al. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J. Clin. Oncol. 2012; 30(24): 2988–94. DOI: https://doi.org/10.1200/JCO.2011.41.4466
  10. Al-Saleem T., Al-Mondhiry H. Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. Blood 2005; 105(6): 2274–80. DOI: https://doi.org/10.1182/blood-2004-07-2755
  11. Anttila T.I., Lehtinen T., Leinonen M. et al. Serological evidence of an association between chlamydial infections and malignant lymphomas. Br. J. Haematol. 1998; 103(1): 150–6. DOI: https://doi.org/10.1046/j.1365-2141.1998.00942.x
  12. Ishimatsu Y., Mukae H., Matsumoto K. et al. Two cases with pulmonary mucosa-associated lymphoid tissue lymphoma successfully treated with clarithromycin. Chest 2010; 138(3): 730–3. DOI: https://doi.org/10.1378/chest.09-2358
  13. Fujimura M., Chin K., Sekita N. et al. Regression of mucosa-associated lymphoid tissue lymphoma of the bladder after antibiotic therapy: a case report. Hinyokika Kiyo 2008; 54(12): 783–6.
  14. Van den Bosch J., Kropman R.F., Blok P., Wijermans P.W. Disappearance of a mucosa-associated lymphoid tissue (MALT) lymphoma of the urinary bladder after treatment for Helicobacter pylori. Eur. J. Haematol. 2002; 68(3): 187–8. DOI: https://doi.org/10.1034/j.1600-0609.2002.01649.x
  15. Oscier D., Bramble J., Hodges E., Wright D. Regression of mucosaassociated lymphoid tissue lymphoma of the bladder after antibiotic therapy. J. Clin. Oncol. 2002; 20(3): 882. DOI: https://doi.org/10.1200/JCO.2002.20.3.882
  16. Quinn E.R., Chan C.H., Hadlock K.G. et al. The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 2001; 98(13): 3745–9. DOI: https://doi.org/10.1182/blood.V98.13.3745
  17. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 2005; 5(4): 251–62. DOI: https://doi.org/10.1038/nrc1589
  18. Martin S.W., Goodnow C.C. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat. Immunol. 2002; 3(2): 182–8. DOI: https://doi.org/10.1038/ni752
  19. Dogan I., Bertocci B., Vilmont V. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 2009; 10(12): 1292–9. DOI: https://doi.org/10.1038/ni.1814
  20. Vaandrager J.-W., Schuuring Ed., Kluin-Nelemans H.C. et al. DNA fiber fluorescence in situ hybridization analysis of immunoglobulin class switching in B-cell neoplasia: aberrant CH gene rearrangements in follicle center-cell lymphoma. Blood 1998; 92(8): 2871–8. DOI: https://doi.org/10.1182/blood.V92.8.2871
  21. Alizadeh A.A., Eisen M.B., Davis R.E. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403(6769): 503–11. DOI: https://doi.org/10.1038/35000501
  22. Davis R.E., Ngo V.N., Lenz G. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463(7277): 88–92. DOI: https://doi.org/10.1038/nature08638
  23. Lenz G., Nagel I., Siebert R. et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med. 2007; 204(3): 633–43. DOI: https://doi.org/10.1084/jem.20062041
  24. Ruminy P., Etancelin P., Couronne L. et al. The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma. Leukemia 2011; 25(4): 681–8. DOI: https://doi.org/10.1038/leu.2010.302
  25. Klein U., Klein G., Ehlin-Henriksson B. et al. Burkitt’s lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol. Med. 1995; 1(5): 495–505. DOI: https://doi.org/10.1007/BF03401587
  26. Damle R.N., Wasil T., Fais F. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94(6): 1840–7. DOI: https://doi.org/10.1182/blood.V94.6.1840.418k06_1840_1847
  27. Hamblin T.J., Davis Z., Gardiner A. et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94(6): 1848–54. DOI: https://doi.org/10.1182/blood.V94.6.1848.418k05_1848_1854
  28. Nikitin E.A., Pivnik A.V., Sudarikov A.B. et al. A comparison of the forms of chronic lympholeukemia in relation to the mutational status of the genes of the immunoglobulin variable region. Ter. Arkh. 2000; 72(7): 52–6.
  29. Hadzidimitriou A., Agathangelidis A., Darzentas N. et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood 2011; 118(11): 3088–95. DOI: https://doi.org/10.1182/blood-2011-03-343434
  30. Agathangelidis A., Darzentas N., Hadzidimitriou A. et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012; 119(19): 4467–75. DOI: https://doi.org/10.1182/blood-2011-11-393694
  31. Herve M., Xu K., Ng Y.S. et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J. Clin. Invest. 2005; 115(6): 1636–43. DOI: https://doi.org/10.1172/JCI24387
  32. Catera R., Silverman G.J., Hatzi K. et al. Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation. Mol. Med. 2008; 14(11–12): 665–74. DOI: https://doi.org/10.2119/2008-00102.Catera
  33. Chu C.C., Catera R., Zhang L. et al. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 2010; 115(19): 3907–15. DOI: https://doi.org/10.1182/blood-2009-09-244251
  34. Herishanu Y., Perez-Galan P., Liu D. 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): 563–74. DOI: https://doi.org/10.1182/blood-2010-05-284984
  35. Duhren-von Minden M., Ubelhart R., Schneider D. et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012; 489(7415): 309–12. DOI: https://doi.org/10.1038/nature11309
  36. Zhu D., Ottensmeier C.H., Du M.Q. et al. Incidence of potential glycosylation sites in immunoglobulin variable regions distinguishes between subsets of Burkitt’s lymphoma and mucosa-associated lymphoid tissue lymphoma. Br. J. Haematol. 2003; 120(2): 217–22. DOI: https://doi.org/10.1046/j.1365-2141.2003.04064.x
  37. Radcliffe C.M., Arnold J.N., Suter D.M. et al. Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J. Biol. Chem. 2007; 282(10): 7405–15. DOI: https://doi.org/10.1074/jbc.M602690200
  38. CoelhoV., Krysov S., Ghaemmaghami A.M. et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. PNAS 2010; 107(43): 18587–92. DOI: https://doi.org/10.1073/pnas.1009388107
  39. Sachen K.L., Strohman M.J., Singletary J. et al. Self-antigen recognition by follicular lymphoma B-cell receptors. Blood 2012; 120(20): 4182–90. DOI: https://doi.org/10.1182/blood-2012-05-427534
  40. Marcucci F., Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2011; 117(6): 1792–8. DOI: https://doi.org/10.1182/blood-2010-06-275818
  41. Gisbert J.P., Garcia-Buey L., Pajares J.M. et al. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment. Pharmacol. Ther. 2005; 21(6): 653–62. DOI: https://doi.org/10.1111/j.1365-2036.2005.02395.x
  42. Victora G.D., Nussenzweig M.C. Germinal centers. Annu. Rev. Immunol. 2012; 30: 429–57. DOI: https://doi.org/10.1146/annurev-immunol-020711-075032
  43. Clark M.R., Tanaka A., Powers S.E., Veselits M. Receptors, subcellular compartments and the regulation of peripheral B cell responses: the illuminating state of anergy. Mol. Immunol. 2011; 48(11): 1281–6. DOI: https://doi.org/10.1016/j.molimm.2010.10.024
  44. Yang J., Reth M. Oligomeric organization of the B-cell antigen receptor on resting cells. Nature 2010; 467(7314): 465–9. DOI: https://doi.org/10.1038/nature09357
  45. Pierce S.K., Liu W. The tipping points in the initiation of B cell signalling: how small changes make big differences. Nat. Rev. Immunol. 2010; 10(11): 767–77. DOI: https://doi.org/10.1038/nri2853
  46. Reth M. Antigen receptor tail clue. Nature 1989; 338(6214): 383–4. DOI: https://doi.org/10.1038/338383b0
  47. Saijo K., Schmedt C., Su I.H. et al. Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat. Immunol. 2003; 4(3): 274–9. DOI: https://doi.org/10.1038/ni893
  48. Rowley R.B., Burkhardt A.L., Chao H.G. et al. Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation. J. Biol. Chem. 1995; 270(19): 11590–4. DOI: https://doi.org/10.1074/jbc.270.19.11590
  49. Oellerich T., Bremes V., Neumann K. et al. The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85. EMBO J. 2011; 30(17): 3620–34. DOI: https://doi.org/10.1038/emboj.2011.251
  50. Watanabe D., Hashimoto S., Ishiai M. et al. Four tyrosine residues in phospholipase C-gamma 2, identified as BTK-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling. J. Biol. Chem. 2001; 276(42): 38595–601. DOI: https://doi.org/10.1074/jbc.M103675200
  51. Ozdener F., Dangelmaier C., Ashby B. et al. Activation of phospholipase Cgamma2 by tyrosine phosphorylation. Mol. Pharmacol. 2002; 62(3): 672–9. DOI: https://doi.org/10.1124/mol.62.3.672
  52. Shinohara H., Yasuda T., Aiba Y. et al. PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J. Exp. Med. 2005; 202(10): 1423–31. DOI: https://doi.org/10.1084/jem.20051591
  53. Coughlin J.J., Stang S.L., Dower N.A., Stone J.C. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J. Immunol. 2005; 175(11): 7179–84. DOI: https://doi.org/10.4049/jimmunol.175.11.7179
  54. Xu Y., Harder K.W., Huntington N.D. et al. Lyn tyrosine kinase: accentuating the positive and the negative. Immunity 2005; 22(1): 9–18. DOI: https://doi.org/10.1016/S1074-7613(04)00381-4
  55. Deane J.A., Fruman D.A. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu. Rev. Immunol. 2004; 22: 563–98. DOI: https://doi.org/10.1146/annurev.immunol.22.012703.104721
  56. Yuan T.L., Cantley L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27(41): 5497–510. DOI: https://doi.org/10.1038/onc.2008.245
  57. Laplante M., Sabatini D.M. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274–93. DOI: https://doi.org/10.1016/j.cell.2012.03.017
  58. Stone J.C. Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes Cancer 2011; 2(3): 320–34. DOI: https://doi.org/10.1177/1947601911408082
  59. Guo B., Su T.T., Rawlings D.J. Protein kinase C family functions in B-cell activation. Curr. Opin. Immunol. 2004; 16(3): 367–73. DOI: https://doi.org/10.1016/j.coi.2004.03.012
  60. Suzuki A., Kaisho T., Ohishi M. et al. Critical roles of PTEN in B cell homeostasis and immunoglobulin class switch recombination. J. Exp. Med. 2003; 197(5): 657–67. DOI: https://doi.org/10.1084/jem.20021101
  61. O’Neill S.K., Getahun A., Gauld S.B. et al. Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 2011; 35(5): 746–56. DOI: https://doi.org/10.1016/j.immuni.2011.10.011
  62. Pao L.I., Lam K.P., Henderson J.M. et al. B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 2007; 27(1): 35–48. DOI: https://doi.org/10.1016/j.immuni.2007.04.016
  63. Liu C., Bai X., Wuet J. et al. N-wasp is essential for the negative regulation of B cell receptor signaling. PLoS Biol. 2013; 11(11): e1001704. DOI: https://doi.org/10.1371/journal.pbio.1001704
  64. Ingley E. Src family kinases: regulation of their activities, levels and identification of new pathways. Biochim. Biophys. Acta 2008; 1784(1): 56–65. DOI: https://doi.org/10.1016/j.bbapap.2007.08.012
  65. Lam K.P., Kuhn R., Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 1997; 90(6): 1073–83. DOI: https://doi.org/10.1016/S0092-8674(00)80373-6
  66. Kraus M., Alimzhanov M.B., Rajewsky N., Rajewsky K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell 2004; 117(6): 787–800. DOI: https://doi.org/10.1016/j.cell.2004.05.014
  67. Srinivasan L., Sasaki Y., Calado D.P. et al. PI3 kinase signals BCRdependent mature B cell survival. Cell 2009; 139(3): 573–86. DOI: https://doi.org/10.1016/j.cell.2009.08.041
  68. Baracho G.V., Miletic A.V., Omori S.A. et al. Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation. Curr. Opin. Immunol. 2011; 23(2): 178–83. DOI: https://doi.org/10.1016/j.coi.2011.01.001
  69. Ramadani F., Bolland D.J., Garcon F. et al. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci. Signal. 2010; 3(134): ra60. DOI: https://doi.org/10.1126/scisignal.2001104
  70. Ngo V.N., Davis R.E., Lamy L. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 2006; 441(7089): 106–10. DOI: https://doi.org/10.1038/nature04687
  71. Lenz G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319(5870): 1676–9. DOI: https://doi.org/10.1126/science.1153629
  72. Davis R.E., Davis E., Ngo V.N. et al. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 2001; 194(12): 1861–74. DOI: https://doi.org/10.1084/jem.194.12.1861
  73. Rawlings D.J., Sommer K., Moreno-Garcia M.E. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat. Rev. Immunol. 2006; 6(11): 799–812. DOI: https://doi.org/10.1038/nri1944
  74. Bajpai U.D., Zhang K., Teutsch M. et al. Bruton’s tyrosine kinase links the B cell receptor to nuclear factor kappaB activation. J. Exp. Med. 2000; 191(10): 1735–44. DOI: https://doi.org/10.1084/jem.191.10.1735
  75. Petro J.B., Rahman S.M.J., Ballard D.W. et al. 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. DOI: https://doi.org/10.1084/jem.191.10.1745
  76. Naylor T.L., Tang H., Ratsch B.A. et al. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. Cancer Res. 2011; 71(7): 2643–53. DOI: https://doi.org/10.1158/0008-5472.CAN-10-2525
  77. Wardemann H., Yurasov S., Schaefer A. et al. Predominant autoantibody production by early human B cell precursors. Science 2003; 301(5638): 1374–7. DOI: https://doi.org/10.1126/science.1086907
  78. Gauld S.B., Benschop R.J., Merrell K.T., Cambier J.C. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat. Immunol. 2005; 6(11): 1160–7. DOI: https://doi.org/10.1038/ni1256
  79. Yarkoni Y., Getahun A., Cambier J.C. Molecular underpinning of B-cell anergy. Immunol. Rev. 2010; 237(1): 249–63. DOI: https://doi.org/10.1111/j.1600-065X.2010.00936.x
  80. Quach T.D., Manjarrez-Orduno N., Adlowitz D.G. et al. Anergic responses characterize a large fraction of human autoreactive naive B cells expressing low levels of surface IgM. J. Immunol. 2011; 186(8): 4640–8. DOI: https://doi.org/10.4049/jimmunol.1001946
  81. Smedby K.E., Hjalgrim H., Askling J. et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J. Natl. Cancer Inst. 2006; 98(1): 51–60. DOI: https://doi.org/10.1093/jnci/djj004
  82. Rui L., Schmitz R., Ceribelli M., Staudt L.M. Malignant pirates of the immune system. Nat. Immunol. 2011; 12(10): 933–40. DOI: https://doi.org/10.1038/ni.2094
  83. Alfarano A., Indraccolo S., Circostaet P. et al. An alternatively spliced form of CD79b gene may account for altered B-cell receptor expression in Bchronic lymphocytic leukemia. Blood 1999; 93(7): 2327–35. DOI: https://doi.org/10.1182/blood.V93.7.2327.407a08_2327_2335
  84. Schmitz R., Young R.M., Ceribelliet M. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012; 490(7418): 116–20. DOI: https://doi.org/10.1038/nature11378
  85. Sander S., Calado D.P., Srinivasan L. et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell 2012; 22(2): 167–79. DOI: https://doi.org/10.1016/j.ccr.2012.06.012
  86. Evan G.I., Wyllie A.H., Gilbert C.S. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69(1): 119–28. DOI: https://doi.org/10.1016/0092-8674(92)90123-T
  87. Quesada V., Conde L., Villamor N. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 2012; 44(1): 47–52. DOI: https://doi.org/10.1038/ng.1032
  88. Wang L., Lawrence M.S., Wan Y. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 2011; 365(26): 2497–506. DOI: https://doi.org/10.1056/NEJMoa1109016
  89. Puente X.S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475(7354): 101–5. DOI: https://doi.org/10.1038/nature10113
  90. Amrein P.C., Attar E.C., Takvorian T. et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin. Cancer Res. 2011; 17(9): 2977–86. DOI: https://doi.org/10.1158/1078-0432.CCR-10-2879
  91. Friedberg J.W., Sharman J., Sweetenham J. 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. DOI: https://doi.org/10.1182/blood-2009-08-236471
  92. Advani R.H., Buggy J.J., Sharman J.P. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies. J. Clin. Oncol. 2013; 31(1): 88–94. DOI: https://doi.org/10.1200/JCO.2012.42.7906
  93. Wang M.L., Rule S., Martin P. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 2013; 369(6): 507–16.
  94. Wyndham W., Gerecitano J.F., Goy A. et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Blood (ASH Annual Meeting Abstracts) 2012; 120: 686. DOI: https://doi.org/10.1182/blood.V120.21.686.686
  95. Byrd J.C., Furman R.R., Coutre S.E. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2013; 369(1): 32–42. DOI: https://doi.org/10.1056/NEJMoa1215637
  96. Coutre S., Byrd J.C., Furman R.R. et al. Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in patients with previously treated chronic lymphocytic leukemia. J. Clin. Oncol. (ASCO Annual Meeting Abstracts) 2011; 29: 6631. DOI: https://doi.org/10.1200/jco.2011.29.15_suppl.6631
  97. Kahl B., Byrd J.C., Flinn I.W. et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform- selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts) 2010; 116(21): 1777. DOI: https://doi.org/10.1182/blood.V116.21.1777.1777
  98. Zent C.S., LaPlant B.R., Johnston P.B. et al. The treatment of recurrent/ refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer 2010; 116(9): 2201–7. DOI: https://doi.org/10.1002/cncr.25005
  99. Renner C., Zinzani P.L., Gressin R. et al. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica 2012; 97(7): 1085–91. DOI: https://doi.org/10.3324/haematol.2011.053173
  100. Witzig T.E., Reeder C.B., LaPlant B.R. et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011; 25(2): 341–7. DOI: https://doi.org/10.1038/leu.2010.226
  101. Witzig T.E., Geyer S.M., Ghobrial I. et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 2005; 23(23): 5347–56. DOI: https://doi.org/10.1200/JCO.2005.13.466
  102. Smith S.M., van Besien K., Karrison T. et al. Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J. Clin. Oncol. 2010; 28(31): 4740–6. DOI: https://doi.org/10.1200/JCO.2010.29.2813
  103. Bruton O.C. Agammaglobulinemia. Pediatrics 1952; 9(6): 722–8. DOI: https://doi.org/10.1542/peds.9.6.722
  104. Rawlings D.J., Saffran D.C., Tsukada S. et al. Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science 1993; 261(5119): 358–61. DOI: https://doi.org/10.1126/science.8332901
  105. Quek L.S., Bolen J., Watson S.P. A role for Bruton’s tyrosine kinase (Btk) in platelet activation by collagen. Curr. Biol. 1998; 8(20): 1137–40. DOI: https://doi.org/10.1016/S0960-9822(98)70471-3
  106. Kurosaki T., Hikida M. Tyrosine kinases and their substrates in B lymphocytes. Immunol. Rev. 2009; 228(1): 132–48. DOI: https://doi.org/10.1111/j.1600-065X.2008.00748.x
  107. Rawlings D.J., Lin S., Scharenberg A.M. et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996; 271(5250): 822–5. DOI: https://doi.org/10.1126/science.271.5250.822
  108. Mohamed A.J., Yu L., Backesjo C.M. et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol. Rev. 2009; 228(1): 58–73. DOI: https://doi.org/10.1111/j.1600-065X.2008.00741.x
  109. Hantschel O., Rix U., Schmidtet U. et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. PNAS 2007; 104(33): 13283–8. DOI: https://doi.org/10.1073/pnas.0702654104
  110. Pan Z., Scheerens H., Li S.J. et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. Chem. Med. Chem. 2007; 2(1): 58–61. DOI: https://doi.org/10.1002/cmdc.200600221
  111. Honigberg L.A., Smith A.M., Sirisawadet M. 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. U S A 2010; 107(29): 13075–80. DOI: https://doi.org/10.1073/pnas.1004594107
  112. Herman S.E., Gordon A.L., Hertlein E. 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. DOI: https://doi.org/10.1182/blood-2011-01-328484
  113. Ponader S., Chen Sh.-Sh., Buggy J.J. et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119(5): 1182–9. DOI: https://doi.org/10.1182/blood-2011-10-386417
  114. de Rooij M.F., Kuil A., Geest C.R. et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012; 119(11): 2590–4. DOI: https://doi.org/10.1182/blood-2011-11-390989
  115. Mocsai A., Ruland J., Tybulewicz V.L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 2010; 10(6): 387–402. DOI: https://doi.org/10.1038/nri2765
  116. Clemens G.R., Schroeder R.E., Magness S.H. et al. Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res. Clin. Mol. Teratol. 2009; 85(2): 130–6. DOI: https://doi.org/10.1002/bdra.20505
  117. Braselmann S., Taylor V., Zhao H. 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. DOI: https://doi.org/10.1124/jpet.106.109058
  118. Gobessi S., Laurenti L., Longo P.G. et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2009; 23(4): 686–97. DOI: https://doi.org/10.1038/leu.2008.346
  119. Quiroga M.P., Balakrishnan K., Kurtova A.V. 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. DOI: https://doi.org/10.1182/blood-2009-03-212837
  120. So L., Fruman D.A. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem. J. 2012; 442(3): 465–81. DOI: https://doi.org/10.1042/BJ20112092
  121. Okkenhaug K., Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 2003; 3(4): 317–30. DOI: https://doi.org/10.1038/nri1056
  122. Kloo B., Nagel D., Pfeifer M. et al. Critical role of PI3K signaling for NF-kappaB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. PNAS 2011; 108(1): 272–7. DOI: https://doi.org/10.1073/pnas.1008969108
  123. Rudelius M., Pittaluga S., Nishizuka S. et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006; 108(5): 1668–76. DOI: https://doi.org/10.1182/blood-2006-04-015586
  124. Herman S.E., Gordon A.L., Wagner A.J. 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. DOI: https://doi.org/10.1182/blood-2010-02-271171
  125. Hoellenriegel J., Meadows S.A., Sivina M. 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. DOI: https://doi.org/10.1182/blood-2011-05-352492
  126. Lannutti B.J., Meadows S.A., Herman S.E.M. et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011; 117(2): 591–4. DOI: https://doi.org/10.1182/blood-2010-03-275305
  127. Mattmann M.E., Stoops S.L., Lindsley C.W. Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opin. Ther. Pat. 2011; 21(9): 1309–38. DOI: https://doi.org/10.1517/13543776.2011.587959

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  • E.A. Nikitin, PhD, Associate professor, Hematology Research Center, RF MH, Moscow, Russian Federation, ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация, e-mail: eugene_nikitin@mail.ru

Published

01.07.2014

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How to Cite

Nikitin E.A. B-Cell Receptor Signaling Pathway: Mechanisms and Inhibitors. Clinical Oncohematology. Basic Research and Clinical Practice. 2014;7(3):251–263. doi:10.21320/2500-2139-2014-7-3-251-263.

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