Protein kinases: Emerging therapeutic targets in chronic lymphocytic leukemia

Expert Opinion on Investigational Drugs

Volumn 21, Issue 4, 2012, Pages 409-423

  Balakrishnan, Kumudha ^a   Gandhi, Varsha ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

B cell receptor; Chronic lymphocytic leukemia; Protein tyrosine kinase; Receptor tyrosine kinase; Tyrosine kinase inhibitor

Indexed keywords

2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; 2,3 DIHYDRO 2 OXO 3 (4,5,6,7 TETRAHYDRO 1H INDOL 2 YLMETHYLENE) 1H INDOLE 5 SULFONIC ACID DIMETHYLAMIDE; 3 (3,5 DIBROMO 4 HYDROXYBENZYLIDENE) 1,3 DIHYDRO 5 IODO 2 INDOLONE; 4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 4 BENZYL 2 METHYL 1,2,4 THIAZOLIDINE 3,5 DIONE; AEZS 131; AT 514; AVL 292; AVL 292001; B LYMPHOCYTE RECEPTOR; BAFETINIB; BAY 613606; BRUTON TYROSINE KINASE; CAL 101; CNX 774; DASATINIB; FLAVOPIRIDOL; FOSTAMATINIB; GLYCOGEN SYNTHASE KINASE 3 INHIBITOR; MIDOSTAURIN; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MK 2206; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; PCI 32765; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE; PROTEIN KINASE C INHIBITOR; PROTEIN KINASE INHIBITOR; PROTEIN KINASE LYN; PROTEIN KINASE SYK; UNCLASSIFIED DRUG; UNINDEXED DRUG;

CELL FUNCTION; CHRONIC LYMPHATIC LEUKEMIA; ENZYME ACTIVATION; HUMAN; LEUKEMOGENESIS; NONHUMAN; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; B-LYMPHOCYTES; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; SIGNAL TRANSDUCTION;

EID: 84858162638     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2012.668526     Document Type: Review

References (152)

1. Robert Roskoski J. "Protein kinase,". AccessScience. McGraw-Hill Co.; 2008
2. Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science 2002;298:1912-34 (Pubitemid 35425239)
3. Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983;306:277-80 (Pubitemid 14232360)
4. Goldman JM, Melo JV. Chronic myeloid leukemia-advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451-64 (Pubitemid 37211061)
5. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004 (Pubitemid 36302244)
6. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:1532-42 (Pubitemid 34925124)
7. Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002;100:59-66 (Pubitemid 35177429)
8. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911-18 (Pubitemid 27019637)
9. Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2011;118:4313-20
10. Takata M, Sabe H, Hata A, et al. Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways. EMBO J 1994;13:1341-9
11. Kurosaki T. Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 1999;17:555-92 (Pubitemid 29241134)
12. Jiang A, Craxton A, Kurosaki T, Clark EA. Different protein tyrosine kinases are required for B cell antigen receptor-mediated activation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase 1, and p38 mitogen-activated protein kinase. J Exp Med 1998;188:1297-306 (Pubitemid 28478018)
13. Fu C, Turck CW, Kurosaki T, Chan AC. BLNK: a central linker protein in B cell activation. Immunity 1998;9:93-103 (Pubitemid 28361298)
14. Marshall AJ, Niiro H, Yun TJ, Clark EA. Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway. Immunol Rev 2000;176:30-46
15. Hashimoto S, Iwamatsu A, Ishiai M, et al. Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK-functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. Blood 1999;94:2357-64 (Pubitemid 29467683)
16. Contri A, Brunati AM, Trentin L, et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest 2005;115:369-78 (Pubitemid 40385478)
17. Tibaldi E, Brunati AM, Zonta F, et al. Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 2011;25:1768-81
18. Motiwala T, Datta J, Kutay H, et al. Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib. J Cell Biochem 2010;110:846-56
19. Ingley E. Src family kinases: regulation of their activities, levels and identification of new pathways. Biochim Biophys Acta 2008;1784:56-65
20. Hussein K, von Neuhoff N, Busche G, et al. Opposite expression pattern of Src kinase Lyn in acute and chronic haematological malignancies. Ann Hematol 2009;88:1059-67
21. Trentin L, Frasson M, Donella-Deana A, et al. Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia. Blood 2008;112:4665-74
22. Pitini V, Arrigo C, Altavilla G. Dasatinib induces a response in chronic lymphocytic leukemia. Blood 2009;113:498
23. Amrein L, Panasci L, Gibson SB, et al. Primary del 17 chronic lymphocytic leukaemia lymphocytes are hypersensitive to dasatinib in vitro. Br J Haematol 2009;147:396-8
24. Veldurthy A, Patz M, Hagist S, et al. The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. Blood 2008;112:1443-52
25. Amrein PC, Attar EC, Takvorian T, et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2011;17:2977-86
26. Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights 2007;2:93-106
27. Kadia T, Delioukina ML, Kantarjian H, et al. (ASH abstract). Blood 2011;118:2858
28. Turner M, Mee PJ, Costello PS, et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 1995;378:298-302
29. Cheng AM, Rowley B, Pao W, et al. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 1995;378:303-6
30. Young RM, Hardy IR, Clarke RL, et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood 2009;113:2508-16
31. Semichon M, Merle-Beral H, Lang V, Bismuth G. Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells. Leukemia 1997;11:1921-8 (Pubitemid 27485139)
32. Buchner M, Fuchs S, Prinz G, et al. Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res 2009;69:5424-32
33. Gobessi S, Laurenti L, Longo PG, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2009;23:686-97
34. Quiroga MP, Balakrishnan K, Kurtova AV, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009;114:1029-37
35. Longo PG, Laurenti L, Gobessi S, et al. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood 2008;111:846-55
36. Baudot AD, Jeandel PY, Mouska X, et al. The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene 2009;28:3261-73
37. Song Z, Lu P, Furman RR, et al. Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib. Clin Cancer Res 2010;16:587-99
38. 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;115:4497-506
39. Suljagic M, Longo PG, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 2010;116:4894-905
40. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578-85
41. Chu DH, Morita CT, Weiss A. The Syk family of protein tyrosine kinases in T-cell activation and development. Immunol Rev 1998;165:167-80 (Pubitemid 28524211)
42. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003;101:4944-51 (Pubitemid 36857758)
43. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001;194:1639-47 (Pubitemid 33126814)
44. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003;348:1764-75 (Pubitemid 36514707)
45. 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;94:1848-54 (Pubitemid 29430400)
46. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004;351:893-901 (Pubitemid 39096916)
47. Schroers R, Griesinger F, Trumper L, et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia 2005;19:750-8, 0041.1-0041.11 (Pubitemid 40663094)
48. Lanham S, Hamblin T, Oscier D, et al. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 2003;101:1087-93 (Pubitemid 36139383)
49. Kong GH, Bu JY, Kurosaki T, et al. Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. Immunity 1995;2:485-92
50. 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;100:4609-14 (Pubitemid 35429705)
51. Turner M, Schweighoffer E, Colucci F, et al. Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunol Today 2000;21:148-54 (Pubitemid 30122705)
52. Petlickovski A, Laurenti L, Li X, et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 2005;105:4820-7 (Pubitemid 40807309)
53. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 2005;105:2036-41 (Pubitemid 40731789)
54. Gobessi S, Laurenti L, Longo PG, et al. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood 2007;109:2032-9 (Pubitemid 46348203)
55. Latour S, Chow LM, Veillette A. Differential intrinsic enzymatic activity of Syk and Zap-70 protein-tyrosine kinases. J Biol Chem 1996;271:22782-90 (Pubitemid 26304725)
56. Laurenti L, Petlickovski A, Rumi C, et al. Comparison of ZAP-70/Syk mRNA levels with immunoglobulin heavy-chain gene mutation status and disease progression in chronic lymphocytic leukemia. Haematologica 2005;90:1533-40 (Pubitemid 41658766)
57. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7 (Pubitemid 34579158)
58. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005;5:921-9 (Pubitemid 41766781)
59. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005;4:988-1004
60. Ringshausen I, Schneller F, Bogner C, et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in BCLL: association with protein kinase Cdelta. Blood 2002;100:3741-8 (Pubitemid 35303946)
61. Kienle D, Benner A, Krober A, et al. Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes. Blood 2006;107:2090-3 (Pubitemid 43289393)
62. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-19 (Pubitemid 44100518)
63. Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol 2003;121:97-100 (Pubitemid 36461273)
64. Aagaard-Tillery KM, Jelinek DF. Phosphatidylinositol 3-kinase activation in normal human B lymphocytes. J Immunol 1996;156:4543-54
65. Beraud C, Henzel WJ, Baeuerle PA. Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-kappaB activation. Proc Natl Acad Sci USA 1999;96:429-34 (Pubitemid 29061225)
66. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999;401:86-90
67. Andjelic S, Hsia C, Suzuki H, et al. Phosphatidylinositol 3-kinase and NF-kappa B/Rel are at the divergence of CD40-mediated proliferation and survival pathways. J Immunol 2000;165:3860-7 (Pubitemid 32057293)
68. 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;18:1391-400 (Pubitemid 39136749)
69. Edelmann J, Klein-Hitpass L, Carpinteiro A, et al. Bone marrow fibroblasts induce expression of PI3K/NF-kappaB pathway genes and a pro-angiogenic phenotype in CLL cells. Leuk Res 2008;32:1565-72
70. Fernandis AZ, Prasad A, Band H, et al. Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene 2004;23:157-67 (Pubitemid 38142250)
71. Kijima T, Maulik G, Ma PC, et al. Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 2002;62:6304-11 (Pubitemid 35244485)
72. Balakrishnan K, Burger JA, Wierda WG, Gandhi V. AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 2009;113:149-53
73. Niedermeier M, Hennessy BT, Knight ZA, et al. Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood 2009;113:5549-57
74. Meadows SA, Vega F, Kashishian A, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012;119:1897-900
75. Herman SE, Gordon AL, Wagner AJ, 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;116:2078-88
76. Herman SE, Lapalombella R, Gordon AL, et al. The role of phosphatidylinositol 3-kinase-delta in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia. Blood 2011;117:4323-7
77. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;118:3603-12
78. Furman RR, Byrd JC, Brown JR, et al. CAL-101, An isoform-selective inhibitor of phosphatidylinositol 3-Kinase P110delta, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010;116(21):31a
79. Stokoe D, Stephens LR, Copeland T, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997;277:567-70 (Pubitemid 27369005)
80. Alessi DR, Andjelkovic M, Caudwell B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996;15:6541-51 (Pubitemid 26413787)
81. Aoki M, Schetter C, Himly M, et al. The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity. J Biol Chem 2000;275:6267-75 (Pubitemid 30129917)
82. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:2905-27
83. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-68 (Pubitemid 29165088)
84. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-41 (Pubitemid 27456390)
85. Plate JM. PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation. Leuk Lymphoma 2004;45:1519-29 (Pubitemid 38885993)
86. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318-21 (Pubitemid 28524494)
87. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785-9 (Pubitemid 26004411)
88. Kops GJ, Burgering BM. Forkhead transcription factors are targets of signalling by the proto-oncogene PKB (C-AKT). J Anat 2000;197 Pt 4:571-4 (Pubitemid 32051537)
89. Hahn-Windgassen A, Nogueira V, Chen CC, et al. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 2005;280:32081-9 (Pubitemid 41361813)
90. Hirai H, Sootome H, Nakatsuru Y, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010;9:1956-67
91. Tolcher AW YT, Fearen I, Taylor A, et al. A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST). J Clin Oncol 2009;27(15s Suppl):abstract 3503
92. Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 2009;11:102-10
93. Ougolkov AV, Bone ND, Fernandez-Zapico ME, et al. Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood 2007;110:735-42 (Pubitemid 47105412)
94. Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 2004;25:471-80 (Pubitemid 39149703)
95. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72:279-90 (Pubitemid 23044942)
96. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011;117:6287-96
97. Smith CI, Baskin B, Humire-Greiff P, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol 1994;152:557-65 (Pubitemid 24072959)
98. Rawlings DJ, Scharenberg AM, Park H, et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996;271:822-5 (Pubitemid 26058937)
99. Baba Y, Hashimoto S, Matsushita M, et al. BLNK mediates Syk-dependent Btk activation. Proc Natl Acad Sci USA 2001;98:2582-6 (Pubitemid 32209525)
100. Uckun FM. Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. Biochem Pharmacol 1998;56:683-91 (Pubitemid 28454578)
101. Feldhahn N, Rio P, Soh BN, et al. Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells. Proc Natl Acad Sci USA 2005;102:13266-71 (Pubitemid 41325012)
102. Uckun FM, Waddick KG, Mahajan S, et al. BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells. Science 1996;273:1096-100 (Pubitemid 26278163)
103. Vassilev A, Ozer Z, Navara C, et al. Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. J Biol Chem 1999;274:1646-56
104. Uckun F, Ozer Z, Vassilev A. Bruton's tyrosine kinase prevents activation of the anti-apoptotic transcription factor STAT3 and promotes apoptosis in neoplastic B-cells and B-cell precursors exposed to oxidative stress. Br J Haematol 2007;136:574-89 (Pubitemid 46148194)
105. Feldhahn N, Klein F, Mooster JL, et al. Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells. J Exp Med 2005;201:1837-52 (Pubitemid 41002902)
106. Mahajan S, Vassilev A, Sun N, et al. Transcription factor STAT5A is a substrate of Bruton's tyrosine kinase in B cells. J Biol Chem 2001;276:31216-28 (Pubitemid 37384990)
107. Takata M, Kurosaki T. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J Exp Med 1996;184:31-40 (Pubitemid 26247212)
108. Fluckiger AC, Li Z, Kato RM, et al. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. EMBO J 1998;17:1973-85 (Pubitemid 28154527)
109. Imboden JB, Stobo JD. Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores. J Exp Med 1985;161:446-56 (Pubitemid 15142797)
110. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature 1993;361:315-25 (Pubitemid 23041621)
111. Petro JB, Khan WN. Phospholipase C-gamma 2 couples Bruton's tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes. J Biol Chem 2001;276:1715-19 (Pubitemid 32109641)
112. Mahajan S, Ghosh S, Sudbeck EA, et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alphacyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem 1999;274:9587-99
113. Uckun FM, Zheng Y, Cetkovic-Cvrlje M, et al. In vivo pharmacokinetic features, toxicity profile, and chemosensitizing activity of alphacyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide (LFMA13), a novel antileukemic agent targeting Bruton's tyrosine kinase. Clin Cancer Res 2002;8:1224-33 (Pubitemid 34517662)
114. Tibbles HE, Samuel P, Erbeck D, et al. In vivo toxicity and antithrombotic profile of the oral formulation of the antileukemic agent, LFM-A13-F. Arzneimittelforschung 2004;54:330-9 (Pubitemid 38858244)
115. Uckun FM, Tibbles H, Venkatachalam T, et al. Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting antileukemic drug candidate, alpha-cyanobeta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFMA13). Arzneimittelforschung 2007;57:31-46 (Pubitemid 46212986)
116. Kim YJ, Sekiya F, Poulin B, et al. Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2. Mol Cell Biol 2004;24:9986-99 (Pubitemid 39458823)
117. Kawakami Y, Kitaura J, Hata D, et al. Functions of Bruton's tyrosine kinase in mast and B cells. J Leukoc Biol 1999;65:286-90 (Pubitemid 29109698)
118. Hantschel O, Rix U, Schmidt U, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA 2007;104:13283-8 (Pubitemid 47293937)
119. Ponader CS, Buggy JJ, Balakrishnan K, et al. Bruton's tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012;119:1182-9
120. Burger JA, O'Brien S, Fowler N, et al. The bruton's tyrosine kinase inhibitor, PCI-32765, is well tolerated and demonstrates promising clinical activity in Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL): an update on ongoing Phase I studies. Blood 2010;116:57a
121. Evans E, Aslanian S, Karp R, et al. Bruton's Tyrosine Kinase from Bench to Bedside: Covalently Silencing B Cells with AVL-292. 16th Congress of the European Hematology Association; 2011
122. Alkan S, Huang Q, Ergin M, et al. Survival role of protein kinase C (PKC) in chronic lymphocytic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. Am J Hematol 2005;79:97-106 (Pubitemid 40770667)
123. Barragan M, de Frias M, Iglesias-Serret D, et al. Regulation of Akt/PKB by phosphatidylinositol 3-kinase-dependent and-independent pathways in B-cell chronic lymphocytic leukemia cells: role of protein kinase C {beta}. J Leukoc Biol 2006;80:1473-9 (Pubitemid 44904986)
124. Barragan M, Campas C, Bellosillo B, Gil J. Protein kinases in the regulation of apoptosis in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2003;44:1865-70 (Pubitemid 37369618)
125. Kitada S, Zapata JM, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 2000;96:393-7 (Pubitemid 30463354)
126. Snowden RT, Sun XM, Dyer MJ, Cohen GM. Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1. Leukemia 2003;17:1981-9 (Pubitemid 37322128)
127. Thomas A, Pepper C, Hoy T, Bentley P. Bryostatin induces protein kinase C modulation, Mcl-1 up-regulation and phosphorylation of Bcl-2 resulting in cellular differentiation and resistance to drug-induced apoptosis in B-cell chronic lymphocytic leukemia cells. Leuk Lymphoma 2004;45:997-1008 (Pubitemid 38444677)
128. Abrams ST, Lakum T, Lin K, et al. B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood 2007;109:1193-201 (Pubitemid 46220668)
129. Escobar-Diaz E, Lopez-Martin EM, Hernandez del Cerro M, et al. AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-kappaB survival pathway. Leukemia 2005;19:572-9 (Pubitemid 40521162)
130. Ganeshaguru K, Wickremasinghe RG, Jones DT, et al. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica 2002;87:167-76 (Pubitemid 34160623)
131. Virchis A, Ganeshaguru K, Hart S, et al. A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C. Hematol J 2002;3:131-6
132. Marti GE, Stetler-Stevenson M, Grant ND, et al. Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia. Leuk Lymphoma 2011;52:2284-92
133. Holler C, Pinon JD, Denk U, et al. PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia. Blood 2009;113:2791-4
134. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001;410:37-40 (Pubitemid 32225829)
135. Kawauchi K, Ogasawara T, Yasuyama M. Activation of extracellular signal-regulated kinase through B-cell antigen receptor in B-cell chronic lymphocytic leukemia. Int J Hematol 2002;75:508-13
136. Smal C, Lisart S, Maerevoet M, et al. Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2'-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB. Biochem Pharmacol 2007;73:351-8 (Pubitemid 44958372)
137. Pedersen IM, Buhl AM, Klausen P, et al. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. Blood 2002;99:1314-19 (Pubitemid 34547086)
138. Ringshausen I, Dechow T, Schneller F, et al. Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells. Leukemia 2004;18:1964-70 (Pubitemid 40028422)
139. Fecteau JF, Bharati IS, O'Hayre M, et al. Sorafenib-induced apoptosis of chronic lymphocytic leukemia cells is associated with downregulation of RAF and Mcl-1. Mol Med 2012;18:19-28
140. 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;117:882-9
141. Fukuda T, Chen L, Endo T, et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad Sci USA 2008;105:3047-52 (Pubitemid 351723665)
142. Daneshmanesh AH, Mikaelsson E, Jeddi-Tehrani M, et al. Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy. Int J Cancer 2008;123:1190-5
143. Chen LS, Redkar S, Bearss D, et al. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood 2009;114:4150-7
144. Raval A, Tanner SM, Byrd JC, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 2007;129:879-90 (Pubitemid 46813150)
145. Chim CS, Chan WW, Kwong YL. Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias. J Clin Pathol 2008;61:844-7 (Pubitemid 351969730)
146. Yankulov KY, Bentley DL. Regulation of CDK7 substrate specificity by MAT1 and TFIIH. EMBO J 1997;16:1638-46 (Pubitemid 27151959)
147. Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2001;2; RESEARCH0041
148. Tong WG, Chen R, Plunkett W, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol 2010;28:3015-22
149. Lin TS, Ruppert AS, Johnson AJ, et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in
150. Boehrer S, Ades L, Braun T, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 2008;111:2170-80 (Pubitemid 351451531)
151. Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 2010;28:4935-44
152. Roberts AW, Seymour JF, Brown JR, et al. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 inhibition: results of a Phase I Study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 2012;30:488-96