Targeting neoplastic B cells and harnessing microenvironment: The "double face" of ibrutinib and idelalisib

Journal of Hematology and Oncology

Volumn 8, Issue 1, 2015, Pages

  Maffei, Rossana ^a   Fiorcari, Stefania ^a   Martinelli, Silvia ^a   Potenza, Leonardo ^a   Luppi, Mario ^a   Marasca, Roberto ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

B cell lymphoproliferative disease; Clinical efficacy; Ibrutinib; Idelalisib; Immune cells; Microenvironment

Indexed keywords

BENDAMUSTINE; BORTEZOMIB; CYCLOPHOSPHAMIDE; DOXORUBICIN; FLUDARABINE; IBRUTINIB; IDELALISIB; LENALIDOMIDE; PLACEBO; PREDNISONE; RITUXIMAB; TEMSIROLIMUS; VINCRISTINE; ANTINEOPLASTIC AGENT; PROTEIN KINASE INHIBITOR; PURINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; QUINAZOLINONE DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; B CELL NONHODGKIN LYMPHOMA; CHRONIC LYMPHATIC LEUKEMIA; DIARRHEA; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; FOLLICULAR LYMPHOMA; HEMATOLOGIC DISEASE; HUMAN; LARGE CELL LYMPHOMA; LYMPHOCYTOMA; LYMPHOCYTOSIS; MACROPHAGE; MANTLE CELL LYMPHOMA; MARGINAL ZONE LYMPHOMA; NATURAL KILLER CELL; NONHODGKIN LYMPHOMA; OSTEOCLAST; REVIEW; SMALL LYMPHOCYTIC LYMPHOMA; T LYMPHOCYTE; UPPER RESPIRATORY TRACT INFECTION; WALDENSTROEM MACROGLOBULINEMIA; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

ANTINEOPLASTIC AGENTS; HUMANS; KILLER CELLS, NATURAL; PROTEIN KINASE INHIBITORS; PURINES; PYRAZOLES; PYRIMIDINES; QUINAZOLINONES; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84938994190     PISSN: None     EISSN: 17568722     Source Type: Journal    
DOI: 10.1186/s13045-015-0157-x     Document Type: Review

References (85)

1. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2(12):945-56. doi: 10.1038/nri955.
2. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, 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: 10.1200/JCO.2012.42.7906.
3. 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(1):32-42. doi: 10.1056/NEJMoa1215637.
4. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-23. doi: 10.1056/NEJMoa1400376.
5. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015. doi: 10.1182/blood-2014-10-606038.
6. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology. 2014;15(10):1090-9. doi: 10.1016/S1470-2045(14)70335-3.
7. O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. The Lancet Oncology. 2014;15(1):48-58. doi: 10.1016/S1470-2045(13)70513-8.
8. Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A et al. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015. doi: 10.1182/blood-2014-09-585869.
9. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology. 2015;16(2):169-76. doi: 10.1016/S1470-2045(14)71182-9.
10. Maddocks K, Christian B, Jaglowski S, Flynn J, Jones JA, Porcu P, et al. A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;125(2):242-8. doi: 10.1182/blood-2014-08-597914.
11. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-16. doi: 10.1056/NEJMoa1306220.
12. Wilson WH, Gerecitano JF, Goy A, De Vos S, Kenkre VP, Barr PM, 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. 2012;120:686.
13. Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. The Lancet Oncology. 2014;15(9):1019-26. doi: 10.1016/S1470-2045(14)70311-0.
14. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-7. doi: 10.1182/blood-2013-11-535047.
15. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007. doi: 10.1056/NEJMoa1315226.
16. Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123(22):3398-405. doi: 10.1182/blood-2013-11-537555.
17. Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123(22):3406-13. doi: 10.1182/blood-2013-11-538546.
18. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18. doi: 10.1056/NEJMoa1314583.
19. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998;62(5):1034-43. doi: 10.1086/301828.
20. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science. 1993;261(5119):358-61.
21. Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207-13. doi: 10.1182/blood-2013-07-515361.
22. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, 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: 10.1182/blood-2011-10-386417.
23. 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. doi: 10.1182/blood-2011-01-328484.
24. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, 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: 10.1182/blood-2011-11-390989.
25. Herman SE, Sun X, McAuley EM, Hsieh MM, Pittaluga S, Raffeld M, et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia. 2013;27(12):2311-21. doi: 10.1038/leu.2013.131.
26. Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286-95. doi: 10.1182/blood-2014-02-548610.
27. 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(3):649-57. doi: 10.1038/leu.2013.358.
28. Wodarz D, Garg N, Komarova NL, Benjamini O, Keating MJ, Wierda WG, et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood. 2014;123(26):4132-5. doi: 10.1182/blood-2014-02-554220.
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(7277):88-92. doi: 10.1038/nature08638.
30. 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 U S A. 2010;107(29):13075-80. doi: 10.1073/pnas.1004594107.
31. Yang Y, Shaffer 3rd AL, Emre NC, Ceribelli M, Zhang M, Wright G, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723-37. doi: 10.1016/j.ccr.2012.05.024.
32. Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120(9):1877-87. doi: 10.1182/blood-2011-12-396853.
33. Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-kappaB. Cell Signal. 2013;25(1):106-12. doi: 10.1016/j.cellsig.2012.09.008.
34. Sivina M, Kreitman RJ, Arons E, Ravandi F, Burger JA. The Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach. Br J Haematol. 2014;166(2):177-88. doi: 10.1111/bjh.12867.
35. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317-30. doi: 10.1038/nri1056.
36. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci. 2005;30(4):194-204. doi: 10.1016/j.tibs.2005.02.008.
37. 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. doi: 10.1182/blood-2002-02-0539.
38. 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. doi: 10.1182/blood-2010-02-271171.
39. 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. doi: 10.1182/blood-2011-05-352492.
40. Maffei R, Bulgarelli J, Fiorcari S, Martinelli S, Castelli I, Valenti V, et al. Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor. PLoS One. 2014;9(6):e98818. doi: 10.1371/journal.pone.0098818.
41. 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. doi: 10.1016/j.cell.2009.08.041.
42. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Wang D, 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.
43. 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(12):e83830. doi: 10.1371/journal.pone.0083830.
44. Herman SE, Lapalombella R, Gordon AL, Ramanunni A, Blum KA, Jones J, et al. The role of phosphatidylinositol 3-kinase-delta in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia. Blood. 2011;117(16):4323-7. doi: 10.1182/blood-2010-11-315705.
45. Bodo J, Zhao X, Sharma A, Hill BT, Portell CA, Lannutti BJ, et al. The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways. Br J Haematol. 2013;163(1):72-80. doi: 10.1111/bjh.12498.
46. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, 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: 10.1182/blood-2010-03-275305.
47. 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. 2010;116(9):1460-8. doi: 10.1182/blood-2009-06-222943.
48. Bao Y, Zheng J, Han C, Jin J, Han H, Liu Y, et al. Tyrosine kinase Btk is required for NK cell activation. J Biol Chem. 2012;287(28):23769-78. doi: 10.1074/jbc.M112.372425.
49. Ni Gabhann J, Spence S, Wynne C, Smith S, Byrne JC, Coffey B, et al. Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-gamma production by natural killer cells. Clin Immunol. 2012;142(3):373-82. doi: 10.1016/j.clim.2011.12.009.
50. Khurana D, Arneson LN, Schoon RA, Dick CJ, Leibson PJ. Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk. J Immunol. 2007;178(6):3575-82.
51. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, Cheney C, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957-60. doi: 10.1182/blood-2014-01-547869.
52. Roit FD, Engelberts PJ, Taylor RP, Breij EC, 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(1):77-86. doi: 10.3324/haematol.2014.107011.
53. 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(5):1163-7. doi: 10.1038/leu.2014.12.
54. Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med. 2008;205(10):2419-35. doi: 10.1084/jem.20072327.
55. Dong S, Guinn D, Dubovsky JA, Zhong Y, Lehman A, Kutok J, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124(24):3583-6. doi: 10.1182/blood-2014-07-587279.
56. Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008;118(7):2427-37. doi: 10.1172/JCI35017.
57. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;120(7):1412-21. doi: 10.1182/blood-2012-02-411678.
58. Ramsay AG, Evans R, Kiaii S, Svensson L, Hogg N, Gribben JG. Chronic lymphocytic leukemia cells induce defective LFA-1-directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide. Blood. 2013;121(14):2704-14. doi: 10.1182/blood-2012-08-448332.
59. Gorgun G, Ramsay AG, Holderried TA, Zahrieh D, Le Dieu R, Liu F, et al. E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. Proc Natl Acad Sci U S A. 2009;106(15):6250-5. doi: 10.1073/pnas.0901166106.
60. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, 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(15):2539-49. doi: 10.1182/blood-2013-06-507947.
61. Schaeffer EM, Yap GS, Lewis CM, Czar MJ, McVicar DW, Cheever AW, et al. Mutation of Tec family kinases alters T helper cell differentiation. Nat Immunol. 2001;2(12):1183-8. doi: 10.1038/ni734.
62. Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, et al. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity. 1999;11(4):399-409.
63. Amoras AL, Kanegane H, Miyawaki T, Vilela MM. Defective Fc-, CR1- and CR3-mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients. J Investig Allergol Clin Immunol. 2003;13(3):181-8.
64. Mukhopadhyay S, Mohanty M, Mangla A, George A, Bal V, Rath S, et al. Macrophage effector functions controlled by Bruton's tyrosine kinase are more crucial than the cytokine balance of T cell responses for microfilarial clearance. J Immunol. 2002;168(6):2914-21.
65. Jongstra-Bilen J, Puig Cano A, Hasija M, Xiao H, Smith CI, Cybulsky MI. Dual functions of Bruton's tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis. J Immunol. 2008;181(1):288-98.
66. Borge M, Almejun MB, Podaza E, Colado A, Fernandez Grecco H, Cabrejo M et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015. doi: 10.3324/haematol.2014.119669.
67. Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, et al. Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J Cell Sci. 2008;121(Pt 24):4124-33. doi: 10.1242/jcs.032763.
68. Mouchemore KA, Sampaio NG, Murrey MW, Stanley ER, Lannutti BJ, Pixley FJ. Specific inhibition of PI3K p110delta inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS J. 2013;280(21):5228-36. doi: 10.1111/febs.12316.
69. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549-55.
70. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787-95. doi: 10.1172/JCI59643.
71. Ni Gabhann J, Hams E, Smith S, Wynne C, Byrne JC, Brennan K, et al. Btk regulates macrophage polarization in response to lipopolysaccharide. PLoS One. 2014;9(1):e85834. doi: 10.1371/journal.pone.0085834.
72. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362(10):875-85. doi: 10.1056/NEJMoa0905680.
73. Chen J, Yao Y, Gong C, Yu F, Su S, Liu B, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19(4):541-55. doi: 10.1016/j.ccr.2011.02.006.
74. Tsukada N, Burger JA, Zvaifler NJ, Kipps TJ. Distinctive features of "nurselike" cells that differentiate in the context of chronic lymphocytic leukemia. Blood. 2002;99(3):1030-7.
75. Ysebaert L, Fournie JJ. Genomic and phenotypic characterization of nurse-like cells that promote drug resistance in chronic lymphocytic leukemia. Leuk Lymphoma. 2011;52(7):1404-6. doi: 10.3109/10428194.2011.568078.
76. Jia L, Clear A, Liu FT, Matthews J, Uddin N, McCarthy A, et al. Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia. Blood. 2014;123(11):1709-19. doi: 10.1182/blood-2013-10-529610.
77. Filip AA, Cisel B, Koczkodaj D, Wasik-Szczepanek E, Piersiak T, Dmoszynska A. Circulating microenvironment of CLL: are nurse-like cells related to tumor-associated macrophages? Blood Cells Mol Dis. 2013;50(4):263-70. doi: 10.1016/j.bcmd.2012.12.003.
78. Giannoni P, Pietra G, Travaini G, Quarto R, Shyti G, Benelli R, et al. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages. Haematologica. 2014;99(6):1078-87. doi: 10.3324/haematol.2013.091405.
79. Bhattacharya N, Diener S, Idler IS, Rauen J, Habe S, Busch H, et al. Nurse-like cells show deregulated expression of genes involved in immunocompetence. Br J Haematol. 2011;154(3):349-56. doi: 10.1111/j.1365-2141.2011.08747.x.
80. Fiorcari S, Martinelli S, Bulgarelli J, Audrito V, Zucchini P, Colaci E et al. Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia. Haematologica. 2014. doi: 10.3324/haematol.2014.113217.
81. Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell. 2008;132(5):794-806. doi: 10.1016/j.cell.2007.12.037.
82. Lee SH, Kim T, Jeong D, Kim N, Choi Y. The tec family tyrosine kinase Btk Regulates RANKL-induced osteoclast maturation. J Biol Chem. 2008;283(17):11526-34. doi: 10.1074/jbc.M708935200.
83. Danks L, Workman S, Webster D, Horwood NJ. Elevated cytokine production restores bone resorption by human Btk-deficient osteoclasts. J Bone Miner Res. 2011;26(1):182-92. doi: 10.1002/jbmr.210.
84. Shinohara M, Chang BY, Buggy JJ, Nagai Y, Kodama T, Asahara H, et al. The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. Bone. 2014;60:8-15. doi: 10.1016/j.bone.2013.11.025.
85. Bam R, Ling W, Khan S, Pennisi A, Venkateshaiah SU, Li X, et al. Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease. Am J Hematol. 2013;88(6):463-71. doi: 10.1002/ajh.23433.