Передача сигнала через B-клеточный рецептор: механизмы и ингибиторы

ОБЗОРЫ , ,

E.A. Никитин

ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация

Для цитирования: Никитин E.A. Передача сигнала через B-клеточный рецептор: механизмы и ингибиторы. Клин. онкогематол. 2014; 7(3): 251–63.

РЕФЕРАТ

Сигнальный путь В-клеточного рецептора (BCR) имеет ключевое значение в жизнеспособности и дифференцировке нормальных В-лимфоцитов. Клетки лимфоидных опухолей используют различные аспекты этого сигнального пути для обеспечения пролиферации и роста. Они проявляются в разных формах: в форме особой антигенной специфичности BCR, в форме активирующих или, наоборот, ингибирующих мутаций генов, кодирующих белки пути BCR. Целый ряд малых молекул подавляют различные компоненты пути BCR.

В обзоре рассматривается передача сигнала через BCR в норме и патологии, а также ингибиторы тирозинкиназ, которые активно используются в клинических исследованиях, и, возможно, уже скоро изменят тактику ведения больных с лимфоидными опухолями.

Ключевые слова: В-клеточные лимфомы, В-клеточный рецептор, ингибиторы киназ.

Принято в печать: 8 мая 2014 г

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  1. Dameshek W., Schwartz R.S. Leukemia and auto-immunization-some possible relationships. Blood 1959; 14: 1151–8.
  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.
  3. Vasudevan B., Chatterjee M. Lyme borreliosis and skin. Indian J. Dermatol. 2013; 58(3): 167–74.
  4. Schollkopf C., Melbye M., Munksgaard L. et al. Borrelia infection and risk of non-Hodgkin lymphoma. Blood 2008; 111(12): 5524–9.
  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.
  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.
  7. Du M.Q., Isaccson P.G. Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol. 2002; 3(2): 97–104.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  17. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 2005; 5(4): 251–62.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  40. Marcucci F., Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2011; 117(6): 1792–8.
  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.
  42. Victora G.D., Nussenzweig M.C. Germinal centers. Annu. Rev. Immunol. 2012; 30: 429–57.
  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.
  44. Yang J., Reth M. Oligomeric organization of the B-cell antigen receptor on resting cells. Nature 2010; 467(7314): 465–9.
  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.
  46. Reth M. Antigen receptor tail clue. Nature 1989; 338(6214): 383–4.
  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.
  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.
  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.
  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.
  51. Ozdener F., Dangelmaier C., Ashby B. et al. Activation of phospholipase Cgamma2 by tyrosine phosphorylation. Mol. Pharmacol. 2002; 62(3): 672–9.
  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.
  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.
  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.
  55. Deane J.A., Fruman D.A. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu. Rev. Immunol. 2004; 22: 563–98.
  56. Yuan T.L., Cantley L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27(41): 5497–510.
  57. Laplante M., Sabatini D.M. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274–93.
  58. Stone J.C. Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes Cancer 2011; 2(3): 320–34.
  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.
  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.
  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.
  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.
  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.
  64. Ingley E. Src family kinases: regulation of their activities, levels and identification of new pathways. Biochim. Biophys. Acta 2008; 1784(1): 56–65.
  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.
  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.
  67. Srinivasan L., Sasaki Y., Calado D.P. et al. PI3 kinase signals BCRdependent mature B cell survival. Cell 2009; 139(3): 573–86.
  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.
  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.
  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.
  71. Lenz G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319(5870): 1676–9.
  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.
  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.
  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.
  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.
  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.
  77. Wardemann H., Yurasov S., Schaefer A. et al. Predominant autoantibody production by early human B cell precursors. Science 2003; 301(5638): 1374–7.
  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.
  79. Yarkoni Y., Getahun A., Cambier J.C. Molecular underpinning of B-cell anergy. Immunol. Rev. 2010; 237(1): 249–63.
  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.
  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.
  82. Rui L., Schmitz R., Ceribelli M., Staudt L.M. Malignant pirates of the immune system. Nat. Immunol. 2011; 12(10): 933–40.
  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.
  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.
  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.
  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.
  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.
  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.
  89. Puente X.S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475(7354): 101–5.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  103. Bruton O.C. Agammaglobulinemia. Pediatrics 1952; 9(6): 722–8.
  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.
  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.
  106. Kurosaki T., Hikida M. Tyrosine kinases and their substrates in B lymphocytes. Immunol. Rev. 2009; 228(1): 132–48.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  121. Okkenhaug K., Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 2003; 3(4): 317–30.
  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.
  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.
  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.
  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.
  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.
  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.