Modeling the chronic lymphocytic leukemia microenvironment in vitro

References

• Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–3397.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
   PubMed Web of Science ®Google Scholar
• Romano MF, Lamberti A, Tassone P, et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood. 1998;92:990–995.
   PubMed Web of Science ®Google Scholar
• Vogler M, Butterworth M, Majid A, et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009;113:4403–4413.
   PubMed Web of Science ®Google Scholar
• Munk Pedersen I, Reed J. Microenvironmental interactions and survival of CLL B-cells. Leuk Lymphoma. 2004;45:2365–2372.
   PubMed Web of Science ®Google Scholar
• Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood. 2004;103:4389–4395.
   PubMed Web of Science ®Google Scholar
• Chiorazzi N, Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol. 2003;21:841–894.
   PubMed Web of Science ®Google Scholar
• Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–1854.
   PubMed Web of Science ®Google Scholar
• Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105–111.
   PubMed Web of Science ®Google Scholar
• Chen L, Widhopf G, Huynh L, et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2002;100:4609–4614.
   PubMed Web of Science ®Google Scholar
• Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102:1515–1525.
   PubMed Web of Science ®Google Scholar
• Pleiman CM, D'Ambrosio D, Cambier JC. The B-cell antigen receptor complex: structure and signal transduction. Immunol Today. 1994;15:393–399.
   PubMedGoogle Scholar
• Burger JA. Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia. Curr Hematol Malign Rep. 2011;7:26–33.
   Web of Science ®Google Scholar
• Davids MS, Brown JR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:2362–2370.
   PubMed Web of Science ®Google Scholar
• Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118:4313–4320.
   PubMed Web of Science ®Google Scholar
• Burger JA. Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape. Curr Opin Oncol. 2012;24:643–649.
   PubMed Web of Science ®Google Scholar
• Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296:1641–1642.
   PubMed Web of Science ®Google Scholar
• Ruuskanen O, Pittard WB, 3rd, Miller K, et al. Staphylococcus aureus Cowan I-induced immunoglobulin production in human cord blood lymphocytes. J Immunol. 1980;125:411–413.
   PubMed Web of Science ®Google Scholar
• Bernal A. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood. 2001;98:3050–3057.
   PubMed Web of Science ®Google Scholar
• Nédellec S, Renaudineau Y, Bordron A, et al. B cell response to surface IgM cross-linking identifies different prognostic groups of B-chronic lymphocytic leukemia patients. J Immunol. 2005;174:3749–3756.
   PubMed Web of Science ®Google Scholar
• Guarini A, Chiaretti S, Tavolaro S, et al. BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells. Blood. 2008;112:782–792.
   PubMed Web of Science ®Google Scholar
• Muzio M, Apollonio B, Scielzo C, et al. Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood. 2008;112:188–195.
   PubMed Web of Science ®Google Scholar
• 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;117:563–574.
   PubMed Web of Science ®Google Scholar
• Rombout A, Lust S, Offner F, et al. Mimicking the tumour microenvironment of chronic lymphocytic leukaemia in vitro critically depends on the type of B-cell receptor stimulation. Br J Cancer. 2016;114:704–712.
   PubMed Web of Science ®Google Scholar
• Burger JA, Quiroga MP, Hartmann E, et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood. 2009;113:3050–3058.
   PubMed Web of Science ®Google Scholar
• Binder M, Léchenne B, Ummanni R, et al. Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. PLoS One. 2010;5:e15992.
   PubMed Web of Science ®Google Scholar
• Ranheim EA, Kipps TJ. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993;177:925–935.
   PubMed Web of Science ®Google Scholar
• Ahonen C, Manning E, Erickson LD, et al. The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol. 2002;3:451–456.
   PubMed Web of Science ®Google Scholar
• Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733.
   PubMed Web of Science ®Google Scholar
• So T, Croft M. Regulation of PI-3-kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Front Immunol. 2013;4:139.
   PubMed Web of Science ®Google Scholar
• Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001;58:4–43.
   PubMed Web of Science ®Google Scholar
• Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229:152–172.
   PubMed Web of Science ®Google Scholar
• Kitada S, Zapata JM, Andreeff M, et al. Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br J Haematol. 1999;106:995–1004.
   PubMed Web of Science ®Google Scholar
• Mineva ND, Rothstein TL, Meyers JA, et al. CD40 ligand-mediated activation of the de novo RelB NF-kappaB synthesis pathway in transformed B cells promotes rescue from apoptosis. J Biol Chem. 2007;282:17475–17485.
   PubMed Web of Science ®Google Scholar
• Banchereau J, Rousset F. Growing human B lymphocytes in the CD40 system. Nature. 1991;353:678–679.
   PubMed Web of Science ®Google Scholar
• Planken EV, Dijkstra NH, Willemze R, et al. Proliferation of B cell malignancies in all stages of differentiation upon stimulation in the CD40 system. Leukemia. 1996;10:488–493.
   PubMed Web of Science ®Google Scholar
• Cuni S, Perez-Aciego P, Perez-Chacon G, et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004;18:1391–1400.
   PubMed Web of Science ®Google Scholar
• Grdisa M. Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro. Leukemia Res. 2003;27:951–956.
   PubMed Web of Science ®Google Scholar
• Palacios F, Abreu C, Prieto D, et al. Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation. Leukemia. 2015;29:115–125.
   PubMed Web of Science ®Google Scholar
• Hamilton E, Pearce L, Morgan L, et al. Mimicking the tumour microenvironment: three different co-culture systems induce a similar phenotype but distinct proliferative signals in primary chronic lymphocytic leukaemia cells. Br J Haematol. 2012;158:589–599.
   PubMed Web of Science ®Google Scholar
• Panayiotidis P, Jones D, Ganeshaguru K, et al. Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol. 1996;92:97–103.
   PubMed Web of Science ®Google Scholar
• Gabrilove JL. Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies. Oncologist. 2001;6:4–7.
   PubMed Web of Science ®Google Scholar
• Lagneaux L, Delforge A, Bron D, et al. Comparative analysis of cytokines released by bone marrow stromal cells from normal donors and B-cell chronic lymphocytic leukemic patients. Leukemia Lymph. 1995;17:127–133.
   PubMed Web of Science ®Google Scholar
• Lagneaux L, Delforge A, Bron D, et al. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood. 1998;91:2387–2396.
   PubMed Web of Science ®Google Scholar
• Ding W, Nowakowski GS, Knox TR, et al. Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. British Journal of Haematology. 2009;147:471–483.
   PubMed Web of Science ®Google Scholar
• Kay NE, Shanafelt TD, Strege AK, et al. Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch”. Leuk Res. 2007;31:899–906.
   PubMed Web of Science ®Google Scholar
• Buchner M, Baer C, Prinz G, et al. Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood. 2010;115:4497–4506.
   PubMed Web of Science ®Google Scholar
• Lagneaux L, Delforge A, De Bruyn C, et al. Adhesion to bone marrow stroma inhibits apoptosis of chronic lymphocytic leukemia cells. Leuk Lymphoma. 1999;35:445–453.
   PubMed Web of Science ®Google Scholar
• Maffei R, Fiorcari S, Bulgarelli J, et al. Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells. Haematologica. 2012;97:952–960.
   PubMed Web of Science ®Google Scholar
• Zucchetto A, Benedetti D, Tripodo C, et al. CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer Res. 2009;69:4001–4009.
   PubMed Web of Science ®Google Scholar
• Zucchetto A, Vaisitti T, Benedetti D, et al. The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells. Leukemia. 2012;26:1301–1312.
   PubMed Web of Science ®Google Scholar
• Gattei V, Bulian P, Del Principe MI, et al. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood. 2008;111:865–873.
   PubMed Web of Science ®Google Scholar
• Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658–3667.
   PubMed Web of Science ®Google Scholar
• Burger JA, Tsukada N, Burger M, et al. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000;96:2655–2663.
   PubMed Web of Science ®Google Scholar
• Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114:4441–4450.
   PubMed Web of Science ®Google Scholar
• Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–397.
   PubMed Web of Science ®Google Scholar
• Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.
   PubMed Web of Science ®Google Scholar
• Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
   PubMed Web of Science ®Google Scholar
• Decker T, Schneller F, Sparwasser T, et al. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood. 2000;95:999–1006.
   PubMed Web of Science ®Google Scholar
• Jahrsdorfer B, Muhlenhoff L, Blackwell SE, et al. B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res. 2005;11:1490–1499.
   PubMed Web of Science ®Google Scholar
• Wu CC, Castro JE, Motta M, et al. Selection of oligonucleotide aptamers with enhanced uptake and activation of human leukemia B cells. Hum Gene Ther. 2003;14:849–860.
   PubMed Web of Science ®Google Scholar
• Liang X, Moseman EA, Farrar MA, et al. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood. 2010;115:5041–5052.
   PubMed Web of Science ®Google Scholar
• Rozkova D, Novotna L, Pytlik R, et al. Toll-like receptors on B-CLL cells: expression and functional consequences of their stimulation. Int J Cancer. 2010;126:1132–1143.
   PubMed Web of Science ®Google Scholar
• Grandjenette C, Kennel A, Faure GC, et al. Expression of functional toll-like receptors by B-chronic lymphocytic leukemia cells. Haematologica. 2007;92:1279–1281.
   PubMed Web of Science ®Google Scholar
• Fonte E, Apollonio B, Scarfo L, et al. In vitro sensitivity of CLL cells to fludarabine may be modulated by the stimulation of Toll-like receptors. Clin Cancer Res. 2013;19:367–379.
   PubMed Web of Science ®Google Scholar
• Purroy N, Abrisqueta P, Carabia J, et al. Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein. Leukemia. 2014;28:1993–2004.
   PubMed Web of Science ®Google Scholar
• Spaner DE, Masellis A. Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia. 2007;21:53–60.
   PubMed Web of Science ®Google Scholar
• Decker T, Schneller F, Kronschnabl M, et al. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol. 2000;28:558–568.
   PubMed Web of Science ®Google Scholar
• Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–436.
   PubMed Web of Science ®Google Scholar
• Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–1756.
   PubMed Web of Science ®Google Scholar
• Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10.
   PubMed Web of Science ®Google Scholar
• Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–999.
   PubMed Web of Science ®Google Scholar
• Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007;109:703–710.
   PubMed Web of Science ®Google Scholar
• Nishio M. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1. Blood. 2005;106:1012–1020.
   PubMed Web of Science ®Google Scholar
• Hahne M, Kataoka T, Schröter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med. 1998;188:1185–1190.
   PubMed Web of Science ®Google Scholar
• Kern C, Cornuel J-F, Billard C, et al. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood. 2004;103:679–688.
   PubMed Web of Science ®Google Scholar
• Novak AJ. Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood. 2002;100:2973–2979.
   PubMed Web of Science ®Google Scholar
• Shaughnessy J. APRIL showers cause CLL and myeloma to flower. Blood. 2005;106:766–767.
   Web of Science ®Google Scholar
• Haiat S, Billard C, Quiney C, et al. Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia. Immunology. 2006;118:281–292.
   PubMed Web of Science ®Google Scholar
• Ferrer G, Bosch R, Hodgson K, et al. B cell activation through CD40 and IL4R ligation modulates the response of chronic lymphocytic leukaemia cells to BAFF and APRIL. Br J Haematol. 2014;164:570–578.
   PubMed Web of Science ®Google Scholar
• Fluckiger AC, Rossi JF, Bussel A, et al. Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors. Blood. 1992;80:3173–3181.
   PubMed Web of Science ®Google Scholar
• Plate JM, Knospe WH, Harris JE, et al. Normal and aberrant expression of cytokines in neoplastic cells from chronic lymphocytic leukemias. Hum Immunol. 1993;36:249–258.
   PubMed Web of Science ®Google Scholar
• Osinalde N, Moss H, Arrizabalaga O, et al. Interleukin-2 signaling pathway analysis by quantitative phosphoproteomics. J Proteomics. 2011;75:177–191.
   PubMed Web of Science ®Google Scholar
• Decker T, Bogner C, Oelsner M, et al. Antiapoptotic effect of interleukin-2 (IL-2) in B-CLL cells with low and high affinity IL-2 receptors. Ann Hematol. 2010;89:1125–1132.
   PubMed Web of Science ®Google Scholar
• Hivroz C, Grillot-Courvalin C, Brouet JC, et al. Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2. Eur J Immunol. 1986;16:1001–1004.
   PubMed Web of Science ®Google Scholar
• Touw I, Dorssers L, Lowenberg B. The proliferative response of B cell chronic lymphocytic leukemia to interleukin 2: functional characterization of the interleukin 2 membrane receptors. Blood. 1987;69:1667–1673.
   PubMed Web of Science ®Google Scholar
• Trentin L, Zambello R, Agostini C, et al. Expression and regulation of tumor necrosis factor, interleukin-2, and hematopoietic growth factor receptors in B-cell chronic lymphocytic leukemia. Blood. 1994;84:4249–4256.
   PubMed Web of Science ®Google Scholar
• Burke F, Griffin D, Elwood N, et al. The effect of cytokines on cultured mononuclear cells from patients with B cell chronic lymphocytic leukemia. Hematol Oncol. 1993;11:23–33.
   PubMed Web of Science ®Google Scholar
• McManus AP, Desai ZR, Lavabre-Bertrand T. B-cell chronic lymphocytic leukaemia populations respond stochastically to combinations of growth signals in vitro. Leuk Res. 1993;17:477–481.
   PubMed Web of Science ®Google Scholar
• Fluckiger AC, Garrone P, Durand I, et al. Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes. J Exp Med. 1993;178:1473–1481.
   PubMed Web of Science ®Google Scholar
• Grabstein KH, Eisenman J, Shanebeck K, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994;264:965–968.
   PubMed Web of Science ®Google Scholar
• Armitage RJ, Macduff BM, Eisenman J, et al. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol. 1995;154:483–490.
   PubMed Web of Science ®Google Scholar
• Giri JG, Ahdieh M, Eisenman J, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994;13:2822–2830.
   PubMed Web of Science ®Google Scholar
• Trentin L, Zambello R, Facco M, et al. Interleukin-15: a novel cytokine with regulatory properties on normal and neoplastic B lymphocytes. Leukemia Lymph. 1997;27:35–42.
   PubMed Web of Science ®Google Scholar
• Spaner DE, Hammond C, Mena J, et al. Effect of IL-2R beta-binding cytokines on costimulatory properties of chronic lymphocytic leukaemia cells: implications for immunotherapy. Br J Haematol. 2004;127:531–542.
   PubMed Web of Science ®Google Scholar
• Trentin L, Cerutti A, Zambello R, et al. Interleukin-15 promotes the growth of leukemic cells of patients with B-cell chronic lymphoproliferative disorders. Blood. 1996;87:3327–3335.
   PubMed Web of Science ®Google Scholar
• Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57–63.
   PubMed Web of Science ®Google Scholar
• Vosshenrich CA, Di Santo JP. Cytokines: IL-21 joins the gamma(c)-dependent network? Curr Biol. 2001;11:R175–R177.
   PubMed Web of Science ®Google Scholar
• Ozaki K, Spolski R, Ettinger R, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol. 2004;173:5361–5371.
   PubMed Web of Science ®Google Scholar
• Vogelzang A, McGuire HM, Yu D, et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29:127–137.
   PubMed Web of Science ®Google Scholar
• Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57–79.
   PubMed Web of Science ®Google Scholar
• Pascutti MF, Jak M, Tromp JM, et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood. 2013;122:3010–3019.
   PubMed Web of Science ®Google Scholar
• Jahrsdorfer B, Blackwell SE, Wooldridge JE, et al. B-chronic lymphocytic leukemia cells and other B cells can produce granzyme B and gain cytotoxic potential after interleukin-21-based activation. Blood. 2006;108:2712–2719.
   PubMed Web of Science ®Google Scholar
• Hagn M, Blackwell SE, Beyer T, et al. B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21. Int Immunol. 2014;26:383–395.
   PubMed Web of Science ®Google Scholar
• de Totero D, Meazza R, Capaia M, et al. The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. Blood. 2008;111:517–524.
   PubMed Web of Science ®Google Scholar
• Timmerman JM, Byrd JC, Andorsky DJ, et al. A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders. Clin Cancer Res. 2012;18:5752–5760.
   PubMed Web of Science ®Google Scholar
• Noma Y, Sideras P, Naito T, et al. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986;319:640–646.
   PubMed Web of Science ®Google Scholar
• Paul WE, Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol. 1987;5:429–459.
   PubMed Web of Science ®Google Scholar
• Pernis A, Witthuhn B, Keegan AD, et al. Interleukin 4 signals through two related pathways. Proc Natl Acad Sci USA. 1995;92:7971–7975.
   PubMed Web of Science ®Google Scholar
• Takeda K, Tanaka T, Shi W, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996;380:627–630.
   PubMed Web of Science ®Google Scholar
• Carlsson M, Sundstrom C, Bengtsson M, et al. Interleukin 4 strongly augments or inhibits DNA synthesis and differentiation of B-type chronic lymphocytic leukemia cells depending on the co-stimulatory activation and progression signals. Eur J Immunol. 1989;19:913–921.
   PubMed Web of Science ®Google Scholar
• Dancescu M, Rubio-Trujillo M, Biron G, et al. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 1992;176:1319–1326.
   PubMed Web of Science ®Google Scholar
• Panayiotidis P, Ganeshaguru K, Jabbar SA, et al. Interleukin-4 inhibits apoptotic cell death and loss of the bcl-2 protein in B-chronic lymphocytic leukaemia cells in vitro. Br J Haematol. 1993;85:439–445.
   PubMed Web of Science ®Google Scholar
• Crawford DH, Catovsky D. In vitro activation of leukaemic B cells by interleukin-4 and antibodies to CD40. Immunology. 1993;80:40–44.
   PubMed Web of Science ®Google Scholar
• Mainou-Fowler T, Copplestone JA, Prentice AG. Effect of interleukins on the proliferation and survival of B cell chronic lymphocytic leukaemia cells. J Clin Pathol. 1995;48:482–487.
   PubMed Web of Science ®Google Scholar
• Minty A, Chalon P, Derocq JM, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362:248–250.
   PubMed Web of Science ®Google Scholar
• Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol. 2003;111:677–690 (quiz 691).
   PubMed Web of Science ®Google Scholar
• Fluckiger AC, Briere F, Zurawski G, et al. IL-13 has only a subset of IL-4-like activities on B chronic lymphocytic leukaemia cells. Immunology. 1994;83:397–403.
   PubMed Web of Science ®Google Scholar
• Zaninoni A, Imperiali FG, Pasquini C, et al. Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia. Exp Hematol. 2003;31:185–190.
   PubMed Web of Science ®Google Scholar
• Heinrich PC, Behrmann I, Muller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334:297–314.
   PubMed Web of Science ®Google Scholar
• Hazan-Halevy I, Harris D, Liu Z, et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood. 2010;115:2852–2863.
   PubMed Web of Science ®Google Scholar
• Moreno A, Villar ML, Camara C, et al. Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells. Blood. 2001;97:242–249.
   PubMed Web of Science ®Google Scholar
• Buggins AG, Patten PE, Richards J, et al. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia. 2008;22:1084–1087.
   PubMed Web of Science ®Google Scholar
• Mukaida N, Harada A, Matsushima K. Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions. Cytokine Growth Factor Rev. 1998;9:9–23.
   PubMed Web of Science ®Google Scholar
• Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14:6735–6741.
   PubMed Web of Science ®Google Scholar
• Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16:2927–2931.
   PubMed Web of Science ®Google Scholar
• Ghia P, Strola G, Granziero L, et al. Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L + T cells by producing CCL22. Eur J Immunol. 2002;32:1403–1413.
   PubMed Web of Science ®Google Scholar
• Wierda WG, Johnson MM, Do KA, et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. Br J Haematol. 2003;120:452–456.
   PubMed Web of Science ®Google Scholar
• Francia di Celle P, Mariani S, Riera L, et al. Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. Blood. 1996;87:4382–4389.
   PubMed Web of Science ®Google Scholar
• Richardson SJ. 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;107:3584–3592.
   PubMed Web of Science ®Google Scholar
• Burger JA. Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): From understanding the basics towards therapeutic targeting. Sem Cancer Biol. 2010;20:424–430.
   PubMed Web of Science ®Google Scholar
• Ticchioni M, Essafi M, Jeandel PY, et al. Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene. 2007;26:7081–7091.
   PubMed Web of Science ®Google Scholar
• Burgess M, Cheung C, Chambers L, et al. CCL2 and CXCL2 enhance survival of primary chronic lymphocytic leukemia cells in vitro. Leuk Lymphoma. 2012;53:1988–1998.
   PubMed Web of Science ®Google Scholar
• Grammer AC, Lipsky PE. CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms. Adv Immunol. 2000;76:61–178.
   PubMed Web of Science ®Google Scholar
• Neron S, Nadeau PJ, Darveau A, et al. Tuning of CD40-CD154 interactions in human B-lymphocyte activation: a broad array of in vitro models for a complex in vivo situation. Arch Immunol Ther Exp. 2011;59:25–40.
   PubMed Web of Science ®Google Scholar
• Hayden RE, Pratt G, Roberts C, et al. Treatment of chronic lymphocytic leukemia requires targeting of the protective lymph node environment with novel therapeutic approaches. Leukemia Lymph. 2012;53:537–549.
   PubMed Web of Science ®Google Scholar
• Natoni A, O'Dwyer M, Santocanale C. A cell culture system that mimics chronic lymphocytic leukemia cells microenvironment for drug screening and characterization. Methods Mol Biol. 2013;986:217–226.
   PubMedGoogle Scholar
• Willimott S, Baou M, Huf S, et al. Separate cell culture conditions to promote proliferation or quiescent cell survival in chronic lymphocytic leukemia. Leuk Lymph. 2007;48:1647–1650.
   PubMed Web of Science ®Google Scholar
• Purroy N, Abrisqueta P, Carabia J, et al. Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating in vivo. Oncotarget. 2015;6:7632–7643.
   PubMed Web of Science ®Google Scholar
• Buggins AG, Pepper C, Patten PE, et al. Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-kappaB activation and de novo gene transcription. Cancer Res. 2010;70:7523–7533.
   PubMed Web of Science ®Google Scholar
• Patten PE, Buggins AG, Richards J, et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood. 2008;111:5173–5181.
   PubMed Web of Science ®Google Scholar
• Plander M, Seegers S, Ugocsai P, et al. Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles. Leukemia. 2009;23:2118–2128.
   PubMed Web of Science ®Google Scholar
• Walsby E, Buggins A, Devereux S, et al. Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia. Blood. 2014;123:3607–3617.
   PubMed Web of Science ®Google Scholar
• Asslaber D, Grössinger EM, Girbl T, et al. Mimicking the microenvironment in chronic lymphocytic leukaemia - where does the journey go? Br J Haematol. 2013;160:711–714.
   PubMed Web of Science ®Google Scholar
• Ghamlouch H, Ouled-Haddou H, Damaj G, et al. A combination of cytokines rescues highly purified leukemic CLL B-cells from spontaneous apoptosis in vitro. PLoS One. 2013;8:e60370.
   PubMed Web of Science ®Google Scholar
• Lafarge ST, Johnston JB, Gibson SB, et al. Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway. Leuk Res. 2014;38:109–115.
   PubMed Web of Science ®Google Scholar
• Koczula KM, Ludwig C, Hayden R, et al. Metabolic plasticity in CLL: adaptation to the hypoxic niche. Leukemia. 2016;30:65–73.
   PubMed Web of Science ®Google Scholar
• Huelsemann MF, Patz M, Beckmann L, et al. Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia. 2015;29:981–984.
   PubMed Web of Science ®Google Scholar
• Maffei R, Martinelli S, Castelli I, et al. Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF. Leuk Res. 2010;34:312–321.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:311–322.
   PubMed Web of Science ®Google Scholar
• Boissard F, Fournie JJ, Quillet-Mary A, et al. Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. Blood Cancer J. 2015;5:e355
   PubMed Web of Science ®Google Scholar
• de Rooij MF, Kuil A, Geest CR, 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;119:2590–2594.
   PubMed Web of Science ®Google Scholar
• Pepper C, Buggins AG, Jones CH, et al. Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kdelta inhibition. Leukemia. 2015;29:744–747.
   PubMed Web of Science ®Google Scholar
• Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94:193–205.
   PubMed Web of Science ®Google Scholar
• Filip AA, Cisel B, Wasik-Szczepanek E. Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes. Clin Exp Med. 2015;15:73–83.
   PubMed Web of Science ®Google Scholar
• Guadagnoli M, Kimberley FC, Phan U, et al. Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. Blood. 2011;117:6856–6865.
   PubMed Web of Science ®Google Scholar
• Messmer D, Fecteau JF, O'Hayre M, et al. Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib. Blood. 2011;117:882–889.
   PubMed Web of Science ®Google Scholar
• McCaig AM, Cosimo E, Leach MT, et al. Dasatinib Inhibits CXCR4 Signaling in Chronic Lymphocytic Leukaemia Cells and Impairs Migration Towards CXCL12. PLoS One. 2012;7:e48929.
   PubMed Web of Science ®Google Scholar
• Hoellenriegel J, Coffey GP, Sinha U, et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia. 2012;26:1576–1583.
   PubMed Web of Science ®Google Scholar