Microenvironment dependency in Chronic Lymphocytic Leukemia: The basis for new targeted therapies

Pharmacology and Therapeutics

Volumn 144, Issue 3, 2014, Pages 338-348

  Ten Hacken, Elisa ^a   Burger, Jan A ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

B cell receptor; BTK; Chronic Lymphocytic Leukemia; CXCL12; CXCR4; Microenvironment; Nurselike cells; PI3K ; Stromal cells; SYK

Indexed keywords

B LYMPHOCYTE RECEPTOR; BUPARLISIB; CHEMOKINE RECEPTOR CXCR4; DASATINIB; DUVELISIB; IBRUTINIB; IDELALISIB; IMMUNOMODULATING AGENT; LENALIDOMIDE; MACROPHAGE MIGRATION INHIBITION FACTOR; RITUXIMAB; STROMAL CELL DERIVED FACTOR 1; AGAMMAGLOBULINAEMIA TYROSINE KINASE; ANTINEOPLASTIC AGENT; CXCL12 PROTEIN, HUMAN; CXCR4 PROTEIN, HUMAN; LYMPHOCYTE ANTIGEN RECEPTOR; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE; PROTEIN TYROSINE KINASE;

ARTICLE; BONE MARROW STROMA CELL; CANCER SURVIVAL; CANCER THERAPY; CD4+ T LYMPHOCYTE; CHRONIC LYMPHATIC LEUKEMIA; ENDOTHELIUM CELL; HUMAN; LYMPHOCYTE COUNT; MACROPHAGE; MONOCYTE; NATURAL KILLER CELL; NONHUMAN; OVERALL SURVIVAL; PATHOGENESIS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; IMMUNOLOGY; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY;

ANTINEOPLASTIC AGENTS; CHEMOKINE CXCL12; CLASS IA PHOSPHATIDYLINOSITOL 3-KINASE; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MOLECULAR TARGETED THERAPY; PROTEIN-TYROSINE KINASES; RECEPTORS, ANTIGEN, B-CELL; RECEPTORS, CXCR4; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84908686557     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2014.07.003     Document Type: Review

References (175)

1. Abrams, S. T., Lakum, T., Lin, K., Jones, G.M., Treweeke, A. T., Farahani, M., et al. (2007). B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood 109, 1193-1201.
2. Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., et al. (2013). Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has signifi cant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31, 88-94.
3. Agathangelidis, A., Darzentas, N., Hadzidimitriou, A., Brochet, X., Murray, F., Yan, X. J., et al. (2012). Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classi fication with implications for targeted therapies. Blood 119, 4467-4475.
4. Amrein, P. C., Attar, E. C., Takvorian, T., Hochberg, E. P., Ballen, K. K., Leahy, K. M., et al. (2011). Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 17, 2977-2986.
5. Amrein, L., Shawi, M., Grenier, J., Aloyz, R., & Panasci, L. (2013). The phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in vitro. Int J Cancer 133, 247-252.
6. Andritsos, L., Byrd, J. C., Jones, J. A., Hewes, B., Kipps, T. J., Hsu, F. J., et al. (2010). Preliminary results from a phase I dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia. Blood 116, 1017a.
7. Aydin, S., Grabellus, F., Eisele, L., Mollmann, M., Hanoun, M., Ebeling, P., et al. (2011). Investigating the role of CD38 and functionally related molecular risk factors in the CLL NOD/SCID xenograft model. Eur J Haematol 87, 10-19.
8. Badoux, X., Bueso-Ramos, C., Harris, D., Li, P., Liu, Z., Burger, J., et al. (2011a). Cross-talk between chronic lymphocytic leukemia cells and bone marrow endothelial cells: role of signal transducer and activator of transcription 3. Hum Pathol 42, 1989-2000.
9. Badoux, X. C., Keating, M. J., Wen, S., Lee, B. N., Sivina, M., Reuben, J., et al. (2011b). Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 118, 3489-3498.
10. Barrientos, J. C., Furman, R. R., Leonard, J., Flinn, I., Rai, K., De vos, S., et al. (2013). Update on a phase I study of the selective PI3Kd inhibitor idelalisib (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL. Journal of Clinical Oncology (ASCO Annual Meeting Abstracts) 31 (Suppl.), (abstract 7017).
11. Binder, M., Lechenne, B., Ummanni, R., Scharf, C., Balabanov, S., Trusch, M., et al. (2010). Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. PLoS One 5, e15992.
12. Binder, M., Muller, F., Frick, M., Wehr, C., Simon, F., Leistler, B., et al. (2013). CLL B-cell receptors can recognize themselves: alternative epitopes and structural clues for autostimulatory mechanisms in CLL. Blood 121, 239-241.
13. Bleul, C. C., Fuhlbrigge, R. C., Casasnovas, J. M., Aiuti, A., & Springer, T. A. (1996). A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184, 1101-1109.
14. Borche, L., Lim, A., Binet, J. L., & Dighiero, G. (1990). Evidence that chronic lymphocytic leukemia B lymphocytes are frequently committed to production of natural autoantibodies. Blood 76, 562-569.
15. Brachtl, G., Sahakyan, K., Denk, U., Girbl, T., Alinger, B., Hofbauer, S. W., et al. (2011). Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells. PLoS One 6, e23758.
16. Braselmann, S., Taylor, V., Zhao, H., Wang, S., Sylvain, C., Baluom, M., et al. (2006). R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 319, 998-1008.
17. Broker, B.M., Klajman, A., Youinou, P., Jouquan, J., Worman, C. P., Murphy, J., et al. (1988). Chronic lymphocytic leukemic (CLL) cells secrete multispeci fic autoantibodies. J Autoimmun 1, 469-481.
18. Brooks, S. R., Kirkham, P. M., Freeberg, L., & Carter, R. H. (2004). Binding of cytoplasmic proteins to the CD19 intracellular domain is high affinity, competitive, and multimeric. J Immunol 172, 7556-7564.
19. Brown, J. R., Barrientos, J. C., Barr, P. M., Flinn, I., Burger, J., Salman, Z., et al. (2013). Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study. Blood (ASH Annual Meeting Abstracts) 122. (pp. 525).
20. Brown, J. R., Byrd, J. C., Coutre, S. E., Benson, D. M., Flinn, I. W., Wagner-Johnston, N. D., et al. (2014). Idelalisib, an inhibitor of phosphatidylinositol 3 kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123, 3390-3397.
21. Bulian, P., Shanafelt, T. D., Fegan, C., Zucchetto, A., Cro, L., Nuckel, H., Baldini, L., Kurtova, A. V., Ferrajoli, A., Burger, J. A., Gaidano, G., Del Poeta, G., Pepper, C., Rossi, D., & Gattei, V. (2014). CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J Clin Oncol 32, 897-904.
22. Burger, J. A., & Peled, A. (2009). CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23, 43-52.
23. Burger, J. A., Burger, M., & Kipps, T. J. (1999). Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94, 3658-3667.
24. Burger, J. A., Tsukada, N., Burger, M., Zvaifler, N. J., Dell'Aquila, M., & Kipps, T. J. (2000). Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96, 2655-2663.
25. Burger, J. A., Zvaifler, N. J., Tsukada, N., Firestein, G. S., & Kipps, T. J. (2001). Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J Clin Invest 107, 305-315.
26. Burger, M., Hartmann, T., Krome, M., Rawluk, J., Tamamura, H., Fujii, N., et al. (2005). Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 106, 1824-1830.
27. Burger, J. A., Ghia, P., Rosenwald, A., & Caligaris-Cappio, F. (2009a). Themicroenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood 114, 3367-3375.
28. Burger, J. A., Quiroga, M. P., Hartmann, E., Burkle, A., Wierda, W. G., Keating, M. J., et al. (2009b). 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 113, 3050-3058.
29. Burger, J. A., Keating, M. J., Wierda, W. G., Hoellenriegel, J., Jeyakumar, G., Ferrajoli, A., et al. (2013). Ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients. Blood (ASH Annual Meeting Abstracts) 122. (pp. 675).
30. Burke, R. T., Meadows, S., Loriaux, M. M., Currie, K. S., Mitchell, S. A., Maciejewski, P., et al. (2014). A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget 5, 908-915.
31. Burkle, A., Niedermeier, M., Schmitt-Graff, A., Wierda, W. G., Keating, M. J., & Burger, J. A. (2007). Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood 110, 3316-3325.
32. Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., et al. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369, 32-42.
33. Bystry, R. S., Aluvihare, V., Welch, K. A., Kallikourdis, M., & Betz, A. G. (2001). B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2, 1126-1132.
34. Cai, Q. C., Liao, H., Lin, S. X., Xia, Y., Wang, X. X., Gao, Y., et al. (2012). High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma. Med Oncol 29, 2317-2322.
35. Calissano, C., Damle, R. N., Hayes, G., Murphy, E. J., Hellerstein, M. K., Moreno, C., et al. (2009). In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia. Blood 114, 4832-4842.
36. Carsetti, L., Laurenti, L., Gobessi, S., Longo, P. G., Leone, G., & Efremov, D. G. (2009). Phosphorylation of the activation loop tyrosines is required for sustained Syk signaling and growth factor-independent B-cell proliferation. Cell Signal 21, 1187-1194.
37. Chan, V.W., Meng, F., Soriano, P., DeFranco, A. L., & Lowell, C. A. (1997). Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity 7, 69-81.
38. Chanan-Khan, A., Miller, K. C., Lawrence, D., Padmanabhan, S., Miller, A., Hernandez- Illatazurri, F., et al. (2011). Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 117, 2127-2135.
39. + cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib inmantle cell lymphoma patients. Blood 122, 2412-2424.
40. Chen, L., Widhopf, G., Huynh, L., Rassenti, L., Rai, K. R., Weiss, A., et al. (2002). Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 100, 4609-4614.
41. Chen, C. I., Bergsagel, P. L., Paul, H., Xu, W., Lau, A., Dave, N., et al. (2011). Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 29, 1175-1181.
42. Cheng, S., Ma, J., Guo, A., Lu, P., Leonard, J. P., Coleman, M., et al. (2014). BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 28, 649-657.
43. Chu, C. C., Catera, R., Zhang, L., Didier, S., Agagnina, B.M., Damle, R. N., et al. (2010). Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 115, 3907-3915.
44. Coelho, V., Krysov, S., Steele, A., Sanchez Hidalgo, M., Johnson, P. W., Chana, P. S., et al. (2013). Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function. Blood 122, 2664-2672.
45. Cols, M., Barra, C. M., He, B., Puga, I., Xu, W., Chiu, A., et al. (2012). Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL, and CD40L. J Immunol 188, 6071-6083.
46. Contri, A., Brunati, A. M., Trentin, L., Cabrelle, A., Miorin, M., Cesaro, L., et al. (2005). Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest 115, 369-378.
47. Cooper, J. A., & Howell, B. (1993). The when and how of Src regulation. Cell 73, 1051-1054.
48. Cornall, R. J., Cyster, J. G., Hibbs, M. L., Dunn, A. R., Otipoby, K. L., Clark, E. A., et al. (1998). Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8, 497-508.
49. Coscia, M., Vitale, C., Peola, S., Foglietta, M., Rigoni, M., Griggio, V., et al. (2012). Dysfunctional Vgamma9Vdelta2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells. Blood 120, 3271-3279.
50. Coutre, S., Leonard, J., Furman, R., Flinn, I., De Vos, S., Rai, K., et al. (2013). Update on a phase 1 study of the selective PI3K-delta inhibitor, idelalisib (GS-1101) in combination with ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia. Haematologica (EHA Annual Meeting) 98 (s1), (abstract S1150).
51. Damle, R. N., Wasil, T., Fais, F., Ghiotto, F., Valetto, A., Allen, S. L., et al. (1999). Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840-1847.
52. Dave, S. S., Wright, G., Tan, B., Rosenwald, A., Gascoyne, R. D., Chan, W. C., et al. (2004). Prediction of survival in follicular lymphoma based on molecular features of tumorinfiltrating immune cells. N Engl JMed 351, 2159-2169.
53. Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., et al. (2010). Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88-92.
54. de Rooij, M. F., Kuil, A., Geest, C. R., Eldering, E., Chang, B. Y., Buggy, J. J., et al. (2012). The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokinecontrolled adhesion and migration in chronic lymphocytic leukemia. Blood 119, 2590-2594.
55. Deaglio, S., Morra, M., Mallone, R., Ausiello, C. M., Prager, E., Garbarino, G., et al. (1998). Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol 160, 395-402.
56. Deaglio, S., Vaisitti, T., Bergui, L., Bonello, L., Horenstein, A. L., Tamagnone, L., et al. (2005). CD38 and CD100 lead a network of surface receptors relaying positive signals for BCLL growth and survival. Blood 105, 3042-3050.
57. Deaglio, S., Vaisitti, T., Aydin, S., Bergui, L., D'Arena, G., Bonello, L., et al. (2007). CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. Blood 110, 4012-4021.
58. Decker, S., Finter, J., Forde, A. J., Kissel, S., Schwaller, J., Mack, T. S., et al. (2014). PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). Mol Cancer Ther 13, 1231-1245.
59. Dubovsky, J. A., Chappell, D. L., Harrington, B. K., Agrawal, K., Andritsos, L. A., Flynn, J. M., et al. (2013). Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing. Blood 122, 3308-3316.
60. Duhren-von Minden, M., Ubelhart, R., Schneider, D., Wossning, T., Bach, M. P., Buchner, M., et al. (2012). Chronic lymphocytic leukaemia is driven by antigen-independent cellautonomous signalling. Nature 489, 309-312.
61. Elices, M. J., Osborn, L., Takada, Y., Crouse, C., Luhowskyj, S., Hemler, M. E., et al. (1990). VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60, 577-584.
62. Farinha, P., Masoudi, H., Skinnider, B. F., Shumansky, K., Spinelli, J. J., Gill, K., et al. (2005). Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106, 2169-2174.
63. Farooqui, M., Aue, G., Valdez, J., Martyr, S., Jones, J., Soto, S., et al. (2013). Single agent ibrutinib (PCI-32765) achieves equally good and durable responses in chronic lymphocytic leukemia (CLL) patients with and without deletion 17p. Blood (ASH Annual Meeting Abstracts) 122. (pp. 673).
64. Ferrajoli, A., Lee, B. N., Schlette, E. J., O'Brien, S. M., Gao, H., Wen, S., et al. (2008). Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111, 5291-5297.
65. Ferrajoli, A., Shanafelt, T. D., Ivan, C., Shimizu, M., Rabe, K. G., Nouraee, N., et al. (2013). Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. Blood 122, 1891-1899.
66. Ferreri, A. J., Guidoboni, M., Ponzoni, M., De Conciliis, C., Dell'Oro, S., Fleischhauer, K., et al. (2004). Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96, 586-594.
67. Fiorcari, S., Brown, W. S., McIntyre, B.W., Estrov, Z., Maffei, R., O'Brien, S., et al. (2013). 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 8, e83830.
68. Friedberg, J. W., Sharman, J., Sweetenham, J., Johnston, P. B., Vose, J. M., Lacasce, A., et al. (2010). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115, 2578-2585.
69. Furman, R. R., Sharman, J. P., Coutre, S. E., Cheson, B. D., Pagel, J. M., Hillmen, P., et al. (2014). Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370, 997-1007.
70. Galustian, C., Meyer, B., Labarthe, M. C., Dredge, K., Klaschka, D., Henry, J., et al. (2009). The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 58, 1033-1045.
71. Gattei, V., Bulian, P., Del Principe, M. I., Zucchetto, A., Maurillo, L., Buccisano, F., et al. (2008). Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood 111, 865-873.
72. Ghia, P., Boussiotis, V. A., Schultze, J. L., Cardoso, A. A., Dorfman, D. M., Gribben, J. G., et al. (1998). Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival. Blood 91, 244-251.
73. Ghosh, A. K., Secreto, C. R., Knox, T. R., Ding, W., Mukhopadhyay, D., & Kay, N. E. (2010). Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. Blood 115, 1755-1764.
74. Ghosh, A. K., Secreto, C., Boysen, J., Sassoon, T., Shanafelt, T. D., Mukhopadhyay, D., et al. (2011). The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood 117, 1928-1937.
75. Gobessi, S., Laurenti, L., Longo, P. G., Carsetti, L., Berno, V., Sica, S., et al. (2009). Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 23, 686-697.
76. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G., & Stevenson, F. K. (1999). Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848-1854.
77. Hamilton, E., Pearce, L., Morgan, L., Robinson, S., Ware, V., Brennan, P., et al. (2012). 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 158, 589-599.
78. Herishanu, Y., Perez-Galan, P., Liu, D., Biancotto, A., Pittaluga, S., Vire, B., et al. (2011). The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117, 563-574.
79. Herman, S. E., Gordon, A. L., Wagner, A. J., Heerema, N. A., Zhao, W., Flynn, J. M., et al. (2010). Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116, 2078-2088.
80. Herman, S. E., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., et al. (2011). Bruton's tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 117, 6287-6296.
81. Herman, S. E., Sun, X., McAuley, E. M., Hsieh, M. M., Pittaluga, S., Raffeld, M., et al. (2013). Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia 27 , 2311-21.
82. Herman, S. E., Niemann, C. U., Farooqui, M., Jones, J., Mustafa, R. Z., Lipsky, A., et al. (2014). Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia 27, 2311-2321.
83. Herve, M., Xu, K., Ng, Y. S., Wardemann, H., Albesiano, E., Messmer, B. T., et al. (2005). Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest 115, 1636-1643.
84. Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., et al. (1995). Multiple defects in the immune system of Lyn-de fi cient mice, culminating in autoimmune disease. Cell 83 , 301-311.
85. Hoellenriegel, J., Meadows, S. A., Sivina, M., Wierda, W. G., Kantarjian, H., Keating, M. J., et al. (2011). The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits Bcell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118, 3603-3612.
86. Hoellenriegel, J., Coffey, G. P., Sinha, U., Pandey, A., Sivina, M., Ferrajoli, A., et al. (2012). Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 26, 1576-1583.
87. Hoellenriegel, J., Zboralski, D., Maasch, C., Rosin, N. Y., Wierda, W. G., Keating, M. J., et al. (2014). The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 123, 1032-1039.
88. Hoogeboom, R., van Kessel, K. P., Hochstenbach, F., Wormhoudt, T. A., Reinten, R. J., Wagner, K., et al. (2013). A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J Exp Med 210, 59-70.
89. Hwang, K. K., Trama, A. M., Kozink, D. M., Chen, X., Wiehe, K., Cooper, A. J., et al. (2014). IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria. PLoS One 9, e90725.
90. IPI-145 shows promise in CLL patients. (2014). Cancer Discov, 4, 136
91. Jain, P., Javdan, M., Feger, F. K., Chiu, P. Y., Sison, C., Damle, R. N., et al. (2012). Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance. Haematologica 97, 599-607.
92. Jia, L., Clear, A., Liu, F. T., Matthews, J., Uddin, N., McCarthy, A., et al. (2014). Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia. Blood 123, 1709-1719.
93. Kater, A. P., Spiering, M., Liu, R. D., Doreen Te Raa, G., Slinger, E., Tonino, S. H., et al. (2014). Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study. Leuk Res 38, 34-41.
94. Kitada, S., Zapata, J. M., Andreeff, M., & Reed, J. C. (1999). Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br J Haematol 106, 995-1004.
95. Kostareli, E., Gounari, M., Janus, A., Murray, F., Brochet, X., Giudicelli, V., et al. (2012). Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity. Leukemia 26, 1127-1131.
96. Krysov, S., Potter, K. N., Mockridge, C. I., Coelho, V., Wheatley, I., Packham, G., et al. (2010). Surface IgM of CLL cells displays unusual glycans indicative of engagement of antigen in vivo. Blood 115, 4198-4205.
97. Krzysiek, R., Lefevre, E. A., Zou, W., Foussat, A., Bernard, J., Portier, A., et al. (1999). Antigen receptor engagement selectively induces macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta chemokine production in human B cells. J Immunol 162, 4455-4463.
98. Kurosaki, T., & Hikida, M. (2009). Tyrosine kinases and their substrates in B lymphocytes. Immunol Rev 228, 132-148.
99. Kurtova, A. V., Balakrishnan, K., Chen, R., Ding, W., Schnabl, S., Quiroga, M. P., et al. (2009). 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 114, 4441-4450.
100. Kutting, B., Bonsmann, G., Metze, D., Luger, T. A., & Cerroni, L. (1997). Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a. J Am Acad Dermatol 36, 311-314.
101. Lad, D. P., Varma, S., Varma, N., Sachdeva, M. U., Bose, P., & Malhotra, P. (2013). Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk Lymphoma 54, 1012-1019.
102. Lagneaux, L., Delforge, A., Bron, D., De Bruyn, C., & Stryckmans, P. (1998). Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 91, 2387-2396.
103. Lanemo Myhrinder, A., Hellqvist, E., Sidorova, E., Soderberg, A., Baxendale, H., Dahle, C., et al. (2008). A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood 111, 3838-3848.
104. Langley, R. R., & Fidler, I. J. (2011). The seed and soil hypothesis revisited-the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128, 2527-2535.
105. Lanham, S., Hamblin, T., Oscier, D., Ibbotson, R., Stevenson, F., & Packham, G. (2003). Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 101, 1087-1093.
106. Lannutti, B. J., Meadows, S. A., Herman, S. E., Kashishian, A., Steiner, B., Johnson, A. J., et al. (2011). CAL-101, a p110{delta} selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117, 591-594.
107. Lapalombella, R., Andritsos, L., Liu, Q., May, S. E., Browning, R., Pham, L. V., et al. (2010). Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway. Blood 115, 2619-2629.
108. Lenz, G., Wright, G., Dave, S. S., Xiao, W., Powell, J., Zhao, H., et al. (2008). Stromal gene signatures in large-B-cell lymphomas. N Engl JMed 359, 2313-2323.
109. Lombardo, L. J., Lee, F. Y., Chen, P., Norris, D., Barrish, J. C., Behnia, K., et al. (2004). Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47, 6658-6661.
110. Lutzny, G., Kocher, T., Schmidt-Supprian, M., Rudelius, M., Klein-Hitpass, L., Finch, A. J., et al. (2013). Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell 23, 77-92.
111. Maffei, R., Fiorcari, S., Bulgarelli, J., Martinelli, S., Castelli, I., Deaglio, S., et al. (2012). Physical contactwith endothelial cells through beta1- and beta2-integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells. Haematologica 97, 952-960.
112. Maffei, R., Bulgarelli, J., Fiorcari, S., Bertoncelli, L., Martinelli, S., Guarnotta, C., et al. (2013). Themonocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation. Haematologica 98, 1115-1123.
113. Maffei, R., Bulgarelli, J., Fiorcari, S., Martinelli, S., Castelli, I., Valenti, V., et al. (2014). Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor. PLoS One 9, e98818.
114. Mainou-Fowler, T., Proctor, S. J., Miller, S., & Dickinson, A. M. (2001). Expression and production of interleukin 4 in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma 42, 689-698.
115. McCaig, A. M., Cosimo, E., Leach, M. T., & Michie, A. M. (2011). Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional pro-survival microenvironmental signals. Br J Haematol 153, 199-211.
116. Messmer, B. T., Messmer, D., Allen, S. L., Kolitz, J. E., Kudalkar, P., Cesar, D., et al. (2005). In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 115, 755-764.
117. Mockridge, C. I., Potter, K. N., Wheatley, I., Neville, L. A., Packham, G., & Stevenson, F. K. (2007). Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 109, 4424-4431.
118. Motta, M., Rassenti, L., Shelvin, B. J., Lerner, S., Kipps, T. J., Keating, M. J., et al. (2005). Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia 19, 1788-1793.
119. Moussay, E., Wang, K., Cho, J. H., van Moer, K., Pierson, S., Paggetti, J., et al. (2011). MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 108, 6573-6578.
120. Negro, R., Gobessi, S., Longo, P. G., He, Y., Zhang, Z. Y., Laurenti, L., et al. (2012). Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. Blood 119, 6278-6287.
121. Nishio, M., Endo, T., Tsukada, N., Ohata, J., Kitada, S., Reed, J. C., et al. (2005). Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 106, 1012-1020.
122. Nishizumi, H., Taniuchi, I., Yamanashi, Y., Kitamura, D., Ilic, D., Mori, S., et al. (1995). Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3, 549-560.
123. O'Brien, S. M., Lamanna, N., Kipps, T. J., Flinn, I., Zelenetz, A. D., Burger, J. A., et al. (2013). A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kd) inhibitor idelalisib (GS-1101) in combination with rituximab ® in treatment-naive patients (pts) > 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Journal of Clinical Oncology (ASCO Annual Meeting Abstracts) 31 (Suppl.), (abstract 7005).
124. O'Brien, S., Furman, R. R., Coutre, S. E., Sharman, J. P., Burger, J. A., Blum, K. A., et al. (2014). Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 15, 48-58.
125. O'Hayre, M., Salanga, C. L., Kipps, T. J., Messmer, D., Dorrestein, P. C., & Handel, T. M. (2010). Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis. PLoS One 5, e11716.
126. Okkenhaug, K., & Vanhaesebroeck, B. (2003). PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 3, 317-330.
127. Osborn, L., Hession, C., Tizard, R., Vassallo, C., Luhowskyj, S., Chi-Rosso, G., et al. (1989). Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59, 1203-1211.
128. Panayiotidis, P., Jones, D., Ganeshaguru, K., Foroni, L., & Hoffbrand, A. V. (1996). Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol 92, 97-103.
129. Paterson, A., Mockridge, C. I., Adams, J. E., Krysov, S., Potter, K. N., Duncombe, A. S., et al. (2012). Mechanisms and clinical signi ficance of BIM phosphorylation in chronic lymphocytic leukemia. Blood 119, 1726-1736.
130. Pighi, C., Gu, T. L., Dalai, I., Barbi, S., Parolini, C., Bertolaso, A., et al. (2011). Phosphoproteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of Bcell receptor signaling. Cell Oncol (Dordr) 34, 141-153.
131. Ponader, S., Chen, S. S., Buggy, J. J., Balakrishnan, K., Gandhi, V., Wierda, W. G., et al. (2012). The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119, 1182-1189.
132. Quiroga, M. P., Balakrishnan, K., Kurtova, A. V., Sivina, M., Keating, M. J., Wierda, W. G., et al. (2009). B cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel Syk inhibitor, R406. Blood 114, 4441-4450.
133. Ramsay, A.G., Johnson, A. J., Lee, A.M., Gorgun, G., LeDieu, R., Blum, W., etal. (2008). Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversedwith an immunomodulating drug. J Clin Invest 118, 2427-2437.
134. Ramsay, A. G., Clear, A. J., Fatah, R., & Gribben, J. G. (2012). Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blockedwith lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 120, 1412-1421.
135. Ramsay, A. G., Evans, R., Kiaii, S., Svensson, L., Hogg, N., & Gribben, J. G. (2013). Chronic lymphocytic leukemia cells induce defective LFA-1-directed T-cellmotility by altering Rho GTPase signaling that is reversible with lenalidomide. Blood 121, 2704-2714.
136. Reinart, N., Nguyen, P. H., Boucas, J., Rosen, N., Kvasnicka, H.M., Heukamp, L., et al. (2012). Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood 121, 812-821.
137. Reinart, N., Nguyen, P. H., Boucas, J., Rosen, N., Kvasnicka, H.M., Heukamp, L., et al. (2013). Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood 121, 812-821.
138. Reiners, K. S., Topolar, D., Henke, A., Simhadri, V. R., Kessler, J., Sauer, M., et al. (2013). Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 121, 3658-3665.
139. Riches, J. C., & Gribben, J. G. (2013). Understanding the immunodefi ciency in chronic lymphocytic leukemia: potential clinical implications. Hematol Oncol Clin North Am 27, 207-235.
140. Riches, J. C., Davies, J. K., McClanahan, F., Fatah, R., Iqbal, S., Agrawal, S., et al. (2013). T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121, 1612-1621.
141. Ringshausen, I., Schneller, F., Bogner, C., Hipp, S., Duyster, J., Peschel, C., et al. (2002). Constitutively activated phosphatidylinositol-3 kinase (PI-3 K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood 100, 3741-3748.
142. Rizzo, R., Audrito, V., Vacca, P., Rossi, D., Brusa, D., Stignani, M., et al. (2014). HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism. Haematologica 99, 888-896.
143. Sachen, K. L., Strohman, M. J., Singletary, J., Alizadeh, A. A., Kattah, N. H., Lossos, C., et al. (2012). Self-antigen recognition by follicular lymphoma B-cell receptors. Blood 120, 4182-4190.
144. Sainz-Perez, A., Gary-Gouy, H., Portier, A., Davi, F., Merle-Beral, H., Galanaud, P., et al. (2006). High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia. Leukemia 20, 498-504.
145. Saouaf, S. J., Mahajan, S., Rowley, R. B., Kut, S. A., Fargnoli, J., Burkhardt, A. L., et al. (1994). Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. Proc Natl Acad Sci U S A 91, 9524-9528.
146. Schulz, A., Toedt, G., Zenz, T., Stilgenbauer, S., Lichter, P., & Seiffert, M. (2011). Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2. Haematologica 96, 408-416.
147. Scielzo, C., Ghia, P., Conti, A., Bachi, A., Guida, G., Geuna, M., et al. (2005). HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with good or poor prognoses. J Clin Invest 115, 1644-1650.
148. Seiffert, M., Schulz, A., Ohl, S., Dohner, H., Stilgenbauer, S., & Lichter, P. (2010). Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo. Blood 116, 4223-4230.
149. Sen, G., Bikah, G., Venkataraman, C., & Bondada, S. (1999). Negative regulation of antigen receptor-mediated signaling by constitutive association of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells. Eur J Immunol 29, 3319-3328.
150. Shaffer, A. L., Yu, X., He, Y., Boldrick, J., Chan, E. P., & Staudt, L. M. (2000). BCL-6 represses genes that function in lymphocyte differentiation, in fl ammation, and cell cycle control. Immunity 13, 199-212.
151. Sivina, M., Hartmann, E., Kipps, T. J., Rassenti, L., Krupnik, D., Lerner, S., et al. (2011). CCL3 (MIP-1alpha) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood 117, 1662-1669.
152. Sivina, M., Hartmann, E., Vasyutina, E., Boucas, J.M., Breuer, A., Keating, M. J., et al. (2012). Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia. Leukemia 26, 1576-1583.
153. Song, Z., Lu, P., Furman, R. R., Leonard, J. P., Martin, P., Tyrell, L., et al. (2010). Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib. Clin Cancer Res 16, 587-599.
154. Stevenson, F. K., Krysov, S., Davies, A. J., Steele, A. J., & Packham, G. (2011). B-cell receptor signaling in chronic lymphocytic leukemia. Blood 118, 4313-4320.
155. Sthoeger, Z. M., Wakai, M., Tse, D. B., Vinciguerra, V. P., Allen, S. L., Budman, D. R., et al. (1989). Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J Exp Med 169, 255-268.
156. Strati, P., Keating, M. J., Wierda, W. G., Badoux, X. C., Calin, S., Reuben, J. M., et al. (2013). Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 122, 734-737.
157. Suarez, F., Lortholary, O., Hermine, O., & Lecuit, M. (2006). Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood 107, 3034-3044.
158. Takata, M., & Kurosaki, T. (1996). A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J Exp Med 184, 31-40.
159. ten Hacken, E., Scielzo, C., Bertilaccio, M. T., Scarfo, L., Apollonio, B., Barbaglio, F., et al. (2013). Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia. Blood 121, 2264-2273.
160. Tibaldi, E., Brunati, A. M., Zonta, F., Frezzato, F., Gattazzo, C., Zambello, R., et al. (2011). Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of Bcell chronic lymphocytic leukemia cells. Leukemia 25, 1768-1781.
161. Troeger, A., Johnson, A. J., Wood, J., Blum, W. G., Andritsos, L. A., Byrd, J. C., et al. (2012). RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans. Blood 119, 4708-4718.
162. Veldurthy, A., Patz, M., Hagist, S., Pallasch, C. P., Wendtner, C. M., Hallek, M., et al. (2008). 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 112, 1443-1452.
163. Veuillen, C., Aurran-Schleinitz, T., Castellano, R., Rey, J., Mallet, F., Orlanducci, F., et al. (2012). Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy. J Clin Immunol 32, 632-646.
164. Walsby, E., Buggins, A., Devereux, S., Jones, C., Pratt, G., Brennan, P., et al. (2014). Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia. Blood 123, 3607-3617.
165. Wayner, E. A., Garcia-Pardo, A., Humphries, M. J., McDonald, J. A., & Carter, W. G. (1989). Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol 109, 1321-1330.
166. Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Musser, T. K., Grossbard, E. B., & Magilavy, D. B. (2010). An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 363, 1303-1312.
167. Wodarz, D., Garg, N., Komarova, N. L., Benjamini, O., Keating, M. J., Wierda, W. G., et al. (2014). Kinetics of chronic lymphocytic leukemia (CLL) cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood 123, 4132-4135.
168. Woyach, J. A., Bojnik, E., Ruppert, A. S., Stefanovski, M. R., Goettl, V.M., Smucker, K. A., et al. (2014). Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 123, 1207-1213.
169. Yan, X. J., Dozmorov, I., Li, W., Yancopoulos, S., Sison, C., Centola, M., et al. (2011). Identifi cation of outcome-correlated cytokine clusters in chronic lymphocytic leukemia. Blood 118, 5201-5210.
170. Young, R. M., & Staudt, L. M. (2013). Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 12, 229-243.
171. Zheng, Y., Cai, Z., Wang, S., Zhang, X., Qian, J., Hong, S., et al. (2009). Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114, 3625-3628.
172. Zonta, F., Pagano, M. A., Trentin, L., Tibaldi, E., Frezzato, F., Gattazzo, C., et al. (2013). Lyn-mediated procaspase 8 dimerization blocks apoptotic signaling in B-cell chronic lymphocytic leukemia. Blood 123 , 875-885.
173. Zucca, E., Bertoni, F., Roggero, E., Bosshard, G., Cazzaniga, G., Pedrinis, E., et al. (1998). Molecular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Engl J Med 338 , 804-810.
174. Zucchetto, A., Benedetti, D., Tripodo, C., Bomben, R., Dal Bo, M., Marconi, D., et al. (2009). 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 69 , 4001-4009.
175. Zucchetto, A., Vaisitti, T., Benedetti, D., Tissino, E., Bertagnolo, V., Rossi, D., et al. (2012). The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells. Leukemia 26, 1301-1312.