New roles for B cell receptor associated kinases: when the B cell is not the target


Targeting of B cell receptor associated kinases (BAKs), such as Bruton’s tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLCɣ). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naïve B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2


  1. 1.

    Teras LR, Desantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes. CA Cancer J Clin. 2016;66:443–59.

  2. 2.

    Jerkeman M, Hallek M, Dreyling M, Thieblemont C, Kimby E, Staudt L. Targeting of B-cell receptor signalling in B-cell malignancies. J Intern Med. 2017;282:415–28.

  3. 3.

    Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol. 2013;13:578–91.

  4. 4.

    Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23:410–21.

  5. 5.

    Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 2016;6:1090–105.

  6. 6.

    Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 2015;75:1675–81.

  7. 7.

    Massó-Vallés D, Jauset T, Soucek L. Ibrutinib repurposing: from B-cell malignancies to solid tumors. Oncoscience. 2016;3:147–8.

  8. 8.

    Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6:270–85.

  9. 9.

    Stiff A, Trikha P, Wesolowski R, Kendra K, Hsu V, Uppati S, et al. Myeloid-derived suppressor cells express Bruton’ s Tyrosine kinase and can be depleted in tumor-bearing hosts by ibrutinib treatment. Cancer Res. 2016;76:2125–37.

  10. 10.

    Sagiv-Barfi I, Kohrt HEK, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112:E966–972.

  11. 11.

    Cheng PC, Dykstra ML, Mitchell RN, Pierce SK. A role for lipid rafts in B cell antigen receptor signaling and antigen targeting. J Exp Med. 1999;190:1549–60.

  12. 12.

    Pierce SK. Lipid rafts and B-cell activation. Nat Rev Immunol. 2002;2:96–105.

  13. 13.

    Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science. 1991;251:192–4.

  14. 14.

    Kawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K, et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature. 2000;404:999–1003.

  15. 15.

    Tauzin S, Ding H, Khatib K, Ahmad I, Burdevet D, van Echten-Deckert G, et al. Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Blood. 2008;111:2310–20.

  16. 16.

    Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, et al. Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling. Proc Natl Acad Sci USA. 1992;89:1118–22.

  17. 17.

    Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov. 2013;12:229–43.

  18. 18.

    Scharenberg AM, Humphries LA, Rawlings DJ. Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol. 2007;7:778–89.

  19. 19.

    Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell. 1995;83:301–11.

  20. 20.

    Ingley E. Functions of the Lyn tyrosine kinase in health and disease. Cell Commun Signal. 2012;10:21.

  21. 21.

    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. 2011;34:141–53.

  22. 22.

    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;132:303–16.

  23. 23.

    Ghobrial IM, McCormick DJ, Kaufmann SH, Leontovich AA, Loegering DA, Dai NT, et al. Proteomic analysis of mantle-cell lymphoma by protein microarray. Blood. 2005;105:3722–30.

  24. 24.

    Rizzatti EG, Falcão 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;130:516–26.

  25. 25.

    Cinar M, Hamedani FS, Mo Z, Cinar B, Amin HM, Alkan S. Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. Leuk Res. 2013;37:1271–7.

  26. 26.

    Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5:251–62.

  27. 27.

    Saba NS, Liu D, Herman SEM, Underbayev C, Tian X, Behrend D, et al. Pathogenic role of B-cell receptor signaling and canonical NF- k B activation in mantle cell lymphoma. Blood. 2016;128:82–93.

  28. 28.

    Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194:1861–74.

  29. 29.

    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;463:88–92.

  30. 30.

    Corso J, Pan K-T, Walter R, Doebele C, Mohr S, Bohnenberger H, et al. Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival. Proc Natl Acad Sci. 2016;113:5688–93.

  31. 31.

    Abrams ST, Lakum T, Lin K, Jones GM, Treweeke AT, Farahani M, et al. B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood. 2007;109:1193–2001.

  32. 32.

    Baudot AD, Jeandel PY, Mouska X, Maurer U, Tartare-Deckert S, Raynaud SD, et al. The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene. 2009;28:3261–73.

  33. 33.

    Contri A, Brunati AM, Trentin L, Cabrelle A, Miorin M, Cesaro L, et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005;115:369–78.

  34. 34.

    Cuní S, Pérez-Aciego P, Pérez-Chacón G, Vargas JA, Sánchez A, Martín-Saavedra FM, et al. A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004;18:1391–1400.

  35. 35.

    Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M, et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia. 2014;28:649–57.

  36. 36.

    Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF- kB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563–75.

  37. 37.

    Mittal AK, Chaturvedi NK, Rai KJ, Gilling-Cutucache CE, Nordgren TM, Moragues M, et al. Chronic lymphocytic leukemia cells in a lymph node microenvironment depict molecular signature associated with an aggressive disease. Mol Med. 2014;20:290–301.

  38. 38.

    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.

  39. 39.

    Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840–7.

  40. 40.

    Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan X, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119:4467–76.

  41. 41.

    Bikos V, Darzentas N, Hadzidimitriou A, Davis Z, Hockley S, Traverse-Glehen A, et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia. 2012;26:1638–46.

  42. 42.

    Sebastián E, Alcoceba M, Balanzategui A, Marín L, Montes-Moreno S, Flores T, et al. Molecular characterization of Immunoglobulin gene rearrangements in diffuse large B-cell lymphoma. Am J Pathol. 2012;181:1879–88.

  43. 43.

    Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood. 2007;109:2032–9.

  44. 44.

    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;107:3584–92.

  45. 45.

    Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger Ja, Blum Ka, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.

  46. 46.

    Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:1–6.

  47. 47.

    Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: A phase 2 consortium trial. Blood. 2018;131:182–90.

  48. 48.

    Chamoun K, Boyle E, Houillier C, Jijakli AAl, Delrieu V, Delwail V. Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: a retrspective case series. Neurology. 2017;88:101–2.

  49. 49.

    Wu H, Wang A, Zhang W, Wang B, Chen C, Wang W, et al. Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells. Oncotarget. 2015;6:31313–22.

  50. 50.

    Byrd JC, Harrington B, O’Brien S, Jones Ja, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:323–32.

  51. 51.

    Chang B, Francesco M, Rooij MDe. Egress of CD19+CD5+cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122:2412–24.

  52. 52.

    Da Roit F, Engelberts PJ, Taylor RP, Breij ECW, Gritti G, Rambaldi A, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: Implications for combination therapy. Haematologica. 2015;100:77–86.

  53. 53.

    Burger JA, Li KW, Keating MJ, Sivina M, Amer AM, Garg N, et al. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib. JCI Insight. 2017;2:e89904.

  54. 54.

    Bagnara D, Kaufman MS, Calissano C, Marsilio S, Patten PEM, Simone R, et al. A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease. Blood. 2011;117:5463–72.

  55. 55.

    Woyach Ja, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. New Eng J Med. 2014;370:2286–94.

  56. 56.

    Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–87.

  57. 57.

    Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ Inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–18.

  58. 58.

    Herman SEM, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078–89.

  59. 59.

    Lannutti BJ, Meadows SA, Herman SEM, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–4.

  60. 60.

    Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, et al. PI3K/p110δ is a novel therapeutic target in multiple myeloma. Blood. 2010;116:1460–8.

  61. 61.

    Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: Insight into disease biology and new targeted therapies. Semin Cancer Biol. 2014;24:71–81.

  62. 62.

    Veldurthy A, Patz M, Hagist S, Pallasch CP, Wendtner C-M, Hallek M, et al. The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. Blood. 2008;112:1443–52.

  63. 63.

    Yang C, Lu P, Lee FY, Chadburn A, Barrientos JC, Leonard JP, et al. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib. Leukemia. 2008;22:1755–66.

  64. 64.

    Kim A, Seong KM, Kang HJ, Park S, Lee S-S. Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance. Oncotarget. 2015;6:38225–38.

  65. 65.

    Boukhiar M-A, Roger C, Tran J, Gressin R, Martin A, Ajchenbaum-Cymbalista F, et al. Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma. Exp Hematol Oncol. 2013;2:4.

  66. 66.

    Mccaig AM, Cosimo E, Leach MT, Michie AM. Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells andimpairs migration towards CXCL12. PLoS ONE. 2012;7:e48929.

  67. 67.

    Liu T-M, Woyach Ja, Zhong Y, Lozanski A, Lozanski G, Dong S, et al. Hypermorphic mutation of phospholipase C, gamma 2 acquired in ibrutinib resistant CLL confers BTK independency upon BCR activation. Blood. 2015;126:61–68.

  68. 68.

    Amrein PC, Attar EC, Takvorian T, Hochberg EP, Ballen KK, Leahy KM, et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res. 2011;17:2977–86.

  69. 69.

    Kater AP, Spiering M, Liu RD, Doreen te Raa G, Slinger E, Tonino SH, et al. Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study. Leuk Res. 2014;38:34–41.

  70. 70.

    Sharman JP, Hawkins M, Kolibaba K, Boxer M, Klein L, Wu M, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015;125:2336–43.

  71. 71.

    Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7:157–70.

  72. 72.

    Barr PM, Saylors GB, Spurgeon SE, Cheson BD, Greenwald DR, OBrien SM, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127:2411–5.

  73. 73.

    Chapuy B, Cheng H, Watahiki A, Ducar MD, Tan Y, Chen L, et al. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biologic heterogeneity of the disease. Blood. 2016;127:2203–13.

  74. 74.

    Jones R, Axelrod MJ, Tumas D, Quéva C, Di Paolo J. Combination Effects of B Cell Receptor Pathway Inhibitors (Entospletinib, ONO/GS-4059, and Idelalisib) and a BCL-2 Inhibitor in Primary CLL Cells. Blood. 2015;126:1749.

  75. 75.

    Burke RT, Meadows S, Loriaux MM, Currie KS, Mitchell SA, Maciejewski P, et al. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget. 2014;5:908–15.

  76. 76.

    Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, Laurenti L, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–201.

  77. 77.

    Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30.

  78. 78.

    Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–5.

  79. 79.

    Bea S, Valdes-Mas R, Navarro A, Salaverria I, Martin-Garcia D, Jares P, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci. 2013;110:18250–5.

  80. 80.

    Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185–97.

  81. 81.

    Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.

  82. 82.

    Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171:481–.e15.

  83. 83.

    Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490:116–20.

  84. 84.

    Lam KP, Kühn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997;90:1073–83.

  85. 85.

    Duhren-von Minden M, Ubelhart R, Schneider D, Wossning T, Bach MP, Buchner M, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489:309–12.

  86. 86.

    Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci. 2002;99:6955–60.

  87. 87.

    Nguyen PH, Fedorchenko O, Rosen N, Koch M, Barthel R, Winarski T, et al. LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia. Cancer Cell. 2016;30:610–22.

  88. 88.

    Holler C, Pin JD, Denk U, Heyder C, Hofbauer S, Greil R, et al. PKCβ is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCβ as a therapeutic target in chronic lymphocytic leukemia. Blood. 2009;113:2791–4.

  89. 89.

    Woyach Ja, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker A, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123:1207–13.

  90. 90.

    Chen TL, Tran M, Lakshmanan A, Harrington BK, Gupta N, Goettl VM, et al. NF-κB p50 (nfkb1) contributes to pathogenesis in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. Blood. 2017;130:376–9.

  91. 91.

    Yanagi S, Inatome R, Ding J, Kitaguchi H, Tybulewicz VLJ, Yamamura H. Syk expression in endothelial cells and their morphologic defects in embryonic Syk-deficient mice Brief report Syk expression in endothelial cells and their morphologic defects in embryonic Syk-deficient mice. Blood. 2010;98:2869–71.

  92. 92.

    Mócsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10:387–402.

  93. 93.

    Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605–35.

  94. 94.

    Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–56.

  95. 95.

    Khan WN, Alt FW, Gerstein RM, Malynn BA, Larsson I, Rathbun G, et al. Defective B cell development and function in Btk-deficient mice. Immunity. 1995;3:283–99.

  96. 96.

    Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994;152:557–65.

  97. 97.

    Lutzny G, Kocher T, Schmidt-Supprian M, Rudelius M, Klein-Hitpass L, Finch AJ, et al. Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo. Cancer Cell. 2013;23:77–92.

  98. 98.

    Harris AW, Pinkert CA, Crawford M, Langdon WY, Brinster RL, Adams JM. The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med. 1988;167:353–71.

  99. 99.

    Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, et al. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood. 2016;127:2732–41.

  100. 100.

    Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517–34.

  101. 101.

    Wiestner A. The role of b-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica. 2015;100:1495–507.

  102. 102.

    Choi M, Kipps T. Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. Cancer J. 2011;18:404–10.

  103. 103.

    Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3δ-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603–12.

  104. 104.

    Okkenhaug K, Burger JA. PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL). Curr Top Microbiol Immunol. 2016;393:123–42.

  105. 105.

    Ten Hacken E, Burger Ja. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment. Biochim Biophys Acta. 2015;1863:401–13.

  106. 106.

    Hantschel O, Rix U, Schmidt U, Bürckstümmer T, Kneidinger M, Schütze G, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA. 2007;104:13283–8.

  107. 107.

    Göckeritz E, Vondey V, Guastafierro A, Pizevska M, Hassenrück F, Neumann L, et al. Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro-environmental dialogue. Br J Haematol. 2017;178:949–53.

  108. 108.

    Niemann CU, Herman SEM, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - Findings from an investigator-initiated phase II study. Clin Cancer Res. 2016;22:1572–82.

  109. 109.

    Fiorcari S, Maffei R, Audrito V, Martinelli S, Ten Hacken E, Zucchini P, et al. Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia. Oncotarget. 2016;7:65968–81.

  110. 110.

    Boissard F, Fournié J-J, Quillet-Mary A, Ysebaert L, Poupot M. Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. Blood Cancer J. 2015;5:e355.

  111. 111.

    Borge M, Almejun MB, Podaza E, Colado A, Grecco HF, Cabrejo M, et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015;100:e140–e142.

  112. 112.

    Colado A, Almejún MB, Podaza E, Risnik D, Stanganelli C, Elías EE, et al. The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. Cancer Immunol Immunother. 2016;66:461–73.

  113. 113.

    Herman SEM, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res. 2015;21:4642–51.

  114. 114.

    Fiorcari S, Brown WS, McIntyre BW, Estrov Z, Maffei R, O’Brien S, et al. The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells. PLoS ONE. 2013;8:e83830.

  115. 115.

    van Attekum MH, Eldering E, Kater AP. Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk. Haematologica. 2017;102:1469–76.

  116. 116.

    Dubovsky JA, Beckwith KA, Natarajan G, Woyach J, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49.

  117. 117.

    Cubillos-Zapata C, Avendaño-Ortiz J, Córdoba R, Hernández-Jiménez E, Toledano V, Diego RPde, et al. Ibrutinib as an anti-tumor immunomodulator in patients with refractory chronic lymphocytic leukemia. Oncoimmunology. 2016;5:e1242544.

  118. 118.

    Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017;112:1175–83.

  119. 119.

    Yin Q, Sivina M, Robins H, Yusko E, Vignali M, O’Brien S, et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol. 2017;198:1740–7.

  120. 120.

    Turtle CJ, Hay KA, Li D, Cherian S, Chen X, Wood, et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Speci fi c Chimeric Antigen Receptor – Modi fied T Cells After Failure of Ibrutinib. J Clin Oncol. 2017;35:3010–20.

  121. 121.

    Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127:1117–28.

  122. 122.

    Gill S, Frey NV, Hexner EO, Lacey SF, Melenhorst JJ, Byrd JC, et al. CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL. J Clin Oncol. 2017;35:7509.

  123. 123.

    Maffei R, Fiorcari S, Martinelli S, Potenza L, Luppi M, Marasca R. Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib. J Hematol Oncol. 2015;8:1–13.

  124. 124.

    Bojarczuk K, Siernicka M, Dwojak M, Bobrowicz M, Pyrzynska B, Gaj P, et al. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia. 2014;28:1163–7.

  125. 125.

    Kohrt HEK, Sagiv-Barfi I, Rafiq S, Herman SEM, Butchar JP, Cheney C, et al. Ibrutinib antagonizes rituximab-dependent NK cell–mediated cytotoxicity Ibrutinib. Blood. 2014;123:1957–60.

  126. 126.

    Lindauer M, Hochhaus A. Small molecules in oncology. Recent Results Cancer Res. 2014;201:27–65.

  127. 127.

    Garcia-Gomez A, Ocio EM, Crusoe E, Santamaria C, Hernández-Campo P, Blanco JF, et al. Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. PLoS ONE. 2012;7:e34914.

  128. 128.

    Soucek L, Buggy JJ, Kortlever R, Adimoolam S, Monclús HA, Allende MTS, et al. Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma. Neoplasia. 2011;13:1093–1100.

  129. 129.

    Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15:7–24.

  130. 130.

    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

  131. 131.

    Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510:407–11.

  132. 132.

    Hillmen P, Munir T, Rawstron A, Brock K, Munoz Vicente S, Yates F, et al. Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy. Blood. 2017;130:428.

Download references

Author information

Correspondence to Michael Hallek.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark