Signal transduction in the chronic leukemias: Implications for targeted therapies

Current Hematologic Malignancy Reports

Volumn 8, Issue 1, 2013, Pages 71-80

  Ahmed, Wesam ^a   Van Etten, Richard A ^a  

^a TUFTS MEDICAL CENTER   (United States)

Author keywords

BCR ABL1; Bosutinib; Chronic myelogenous leukemia; Dasatinib; Ibrutinib; Imatinib; JAK2; Nilotinib; Tyrosine kinase inhibitor

Indexed keywords

5 CHLORO N2 [1 (5 FLUORO 2 PYRIMIDINYL)ETHYL] N4 (5 METHYL 1H PYRAZOL 3 YL) 2,4 PYRIMIDINEDIAMINE; B LYMPHOCYTE RECEPTOR; BCR ABL PROTEIN; CYCLOPHOSPHAMIDE; FLUDARABINE; IBRUTINIB; IDELALISIB; IMATINIB; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; MOMELOTINIB; N TERT BUTYL 3 [5 METHYL 2 [4 [2 (1 PYRROLIDINYL)ETHOXY]PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE SYK; PROTEIN TYROSINE KINASE; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; RESVERATROL; RITUXIMAB; SONIC HEDGEHOG PROTEIN; STAT PROTEIN; STAT5 PROTEIN; THROMBOPOIETIN RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

ARTICLE; AUTOPHOSPHORYLATION; CANCER COMBINATION CHEMOTHERAPY; CANCER STEM CELL; CHRONIC LEUKEMIA; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; HOMOZYGOSITY; HUMAN; MOLECULARLY TARGETED THERAPY; MUTAGENESIS; MYELOID METAPLASIA; MYELOPROLIFERATIVE NEOPLASM; NONHUMAN; PATHOGENESIS; PHILADELPHIA CHROMOSOME NEGATIVE CELL; SIGNAL TRANSDUCTION; THROMBOCYTHEMIA;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84874232992     PISSN: 15588211     EISSN: 1558822X     Source Type: Journal    
DOI: 10.1007/s11899-012-0150-1     Document Type: Article

References (125)

1. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112:4808-17.
2. Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054-61.
3. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103:553-61.
4. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029-35.
5. Okimoto RA, Van Etten RA. Navigating the road toward optimal initial therapy for chronic myeloid leukemia. Curr Opin Hematol. 2011;18:89-97.
6. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319-25.
7. Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121:396-409.
8. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144-8.
9. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97.
10. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-61.
11. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-90.
12. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201-14.
13. Griffin JH, Leung J, Bruner RJ, et al. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci U S A. 2003;100:7830-5.
14. Golub TR, Barker GF, Lovett M, et al. Fusion of the PDGF receptor b to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;77:307-16.
15. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355:2452-66.
16. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-27.
17. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
18. Tefferi A. Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms. N Engl J Med. 2012;366:844-6.
19. bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-30.
20. McWhirter JR, Galasso DL, Wang JYJ. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993;13:7587-95.
21. Smith KM, Yacobi R, Van Etten RA. Autoinhibition of Bcr-Abl through its SH3 domain. Mol Cell. 2003;12:27-37.
22. Pendergast AM, Quilliam LA, Cripe LD, et al. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993;75:175-85.
23. Sattler M, Mohi MG, Pride YB, et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell. 2002;1:479-92.
24. Wohrle FU, Halbach S, Aumann K, et al. Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors. Leukemia. 2012.
25. Ghaffari S, Jagani Z, Kitidis C, et al. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A. 2003;100:6523-8.
26. Jagani Z, Singh A, Khosravi-Far R. FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis. Biochim Biophys Acta. 2008;1785:63-84.
27. Naka K, Hoshii T, Muraguchi T, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676-80.
28. Pellicano F, Cilloni D, Helgason GV, et al. FOXO transcription factor activity is partially retained in quiescent CML stem cells and induced by tyrosine kinase inhibitors in CML progenitor cells. Blood. 2009.
29. Hurtz C, Hatzi K, Cerchietti L, et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med. 2011;208:2163-74.
30. Mayerhofer M, Aichberger KJ, Florian S, et al. Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J. 2005;19:960-2.
31. Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A. 2004;101:3130-5.
32. Janes MR, Limon JJ, So L, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med. 2010;16:205-13.
33. Carayol N, Vakana E, Sassano A, et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A. 2010;107:12469-74.
34. Vakana E, Platanias LC. AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. Oncotarget. 2011;2:1322-8.
35. Inoki K, Li Y, Xu T, et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829-34.
36. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214-26.
37. Puissant A, Robert G, Fenouille N, et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 2010;70:1042-52.
38. Li L, Wang L, Li L, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012;21:266-81.
39. Yuan H, Wang Z, Li L, et al. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood. 2012;119:1904-14.
40. Puil L, Liu J, Gish G, et al. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994;13:764-73.
41. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343-56.
42. Pellicano F, Simara P, Sinclair A, et al. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. Leukemia. 2011;25:1159-67.
43. Mancini M, Veljkovic N, Corradi V, et al. 14-3-3 ligand prevents nuclear import of c-ABL protein in chronic myeloid leukemia. Traffic (Copenhagen, Denmark). 2009;10:637-47.
44. Hess P, Pihan G, Sawyers CL, et al. Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat Genet. 2002;32:201-5.
45. BCR/ABL induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem. 1996;271:31704-10.
46. Moriggl R, Sexl V, Kenner L, et al. Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell. 2005;7:87-99.
47. Sillaber C, Gesbert F, Frank DA, et al. STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells. Blood. 2000;95:2118-25.
48. Scherr M, Chaturvedi A, Battmer K, et al. Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML). Blood. 2006;107:3279-87.
49. Hoelbl A, Schuster C, Kovacic B, et al. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol Med. 2010;2:98-110.
50. Walz C, Ahmed W, Lazarides K, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and Jak2V617F in mice. Blood. 2012;119:3550-60.
51. Xie S, Wang Y, Liu J, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20:6188-95.
52. Samanta AK, Lin H, Sun T, et al. Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res. 2006;66:6468-72.
53. Samanta A, Perazzona B, Chakraborty S, et al. Janus kinase 2 regulates Bcr-Abl signaling in chronic myeloid leukemia. Leukemia. 2011;25:463-72.
54. Wertheim JA, Perera SA, Hammer DA, et al. Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development. Blood. 2003;102:2220-8.
55. Hantschel O, Warsch W, Eckelhart E, et al. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nat Chem Biol. 2012;8:285-93.
56. Traer E, Mackenzie R, Snead J, et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia.2011.
57. Beachy PA, Karhadkar SS, Berman DM. Mending and malignancy. Nature. 2004;431:02.
58. Regl G, Kasper M, Schnidar H, et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64:7724-31.
59. Jagani Z, Dorsch M, Warmuth M. Hedgehog pathway activation in chronic myeloid leukemia. Cell Cycle. 2010;9:3449-56.
60. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14:238-49.
61. Zhang B, Irvine D, Ho YW, et al. Inhibition of chronic myeloid leukemia stem cells by the combination of the Hedgehog pathway inhibitor LDE225 with nilotinib. Blood. 2010;116:514a.
62. Shih A, Schairer A, Barrett CL, et al. Cycling toward leukemia stem cell elimination with a selective sonic hedgehog antagonist. Blood. 2011;118:3776a.
63. Jamieson CHM, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657-67.
64. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103:2794-9.
65. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528-41.
66. Hu Y, Chen Y, Douglas L, et al. Beta-catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia. 2009;23:109-16.
67. Heidel FH, Bullinger L, Feng Z, et al. Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10:412-24.
68. Van Etten RA, Shannon KM. Focus on myeloproliferative diseases and myelodysplastic syndromes. Cancer Cell. 2004;6:547-52.
69. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280:22788-92.
70. Levine RL, Gilliland DG. Myeloproliferative disorders. Blood. 2008;112:2190-8.
71. Abdel-Wahab O, Pardanani A, Bernard OA, et al. Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th international post-ASH symposium. Am J Hematol. 2012;87:562-8.
72. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44:1179-81.
73. Ungureanu D, Wu J, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol. 2011;18:971-6.
74. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-8.
75. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-68.
76. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.
77. Wernig G, Mercher T, Okabe R, et al. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006;107:4274-81.
78. Lacout C, Pisani DF, Tulliez M, et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108:1652-60.
79. Zaleskas VM, Krause DS, Lazarides K, et al. Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS One. 2006;1:e18.
80. Bumm TG, Elsea C, Corbin AS, et al. Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Res. 2006;66:11156-65.
81. Pecquet C, Staerk J, Chaligne R, et al. Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor. Blood. 2010;115:1037-48.
82. Tiedt R, Hao-Shen H, Looser R, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111:3931-40.
83. Xing S, Wanting TH, Zhao W, et al. Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood. 2008;111:5109-17.
84. Shide K, Shimoda HK, Kumano T, et al. Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia. 2008;22:87-95.
85. Akada H, Yan D, Zou H, et al. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood. 2010;115:3589-97.
86. Marty C, Lacout C, Martin A, et al. Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice. Blood. 2010;116:783-7.
87. Li J, Spensberger D, Ahn JS, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 2010;116:1528-38.
88. Mullally A, Lane SW, Ball B, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010;17:584-96.
89. Li J, Kent DG, Chen E, et al. Mouse models of myeloproliferative neoplasms: JAK of all grades. Dis Model Mech. 2011;4:311-7.
90. Scott LM, Scott MA, Campbell PJ, et al. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood. 2006;108:2435-7.
91. Godfrey AL, Chen E, Pagano F, et al. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood. 2012;120:2704-7.
92. Anand S, Stedham F, Beer P, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood. 2011;118:177-81.
93. Yan D, Hutchison RE, Mohi G. Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood. 2012;119:3539-49.
94. Reilly JT. Idiopathic myelofibrosis: pathogenesis to treatment. Hematol Oncol Clin N Am. 2006;24:56-63.
95. Martyre MC, Romquin N, Le Bousse-Kerdiles MC, et al. Transforming growth factor-beta and megakaryocytes in the pathogenesis of idiopathic myelofibrosis. Br J Haematol. 1994;88:9-16.
96. Yan XQ, Lacey D, Fletcher F, et al. Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood. 1995;86:4025-33.
97. Villeval JL, Cohen-Solal K, Tulliez M, et al. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood. 1997;90:4369-83.
98. Yan XQ, Lacey D, Hill D, et al. A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood. 1996;88:402-9.
99. Chagraoui H, Komura E, Tulliez M, et al. Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood. 2002;100:3495-503.
100. Tyner JW, Bumm TG, Deininger J, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115:5232-40.
101. Zaleskas VM, Chan WW, Evangelista P, et al. A selective and potent oral inhibitor of the JAK2 tyrosine kinase reverses polycythemia and leukocytosis induced by JAK2 V617F in a mouse model. Blood. 2007;110:557a.
102. Koppikar P, Abdel-Wahab O, Hedvat C, et al. Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis. Blood. 2010;115:2919-27.
103. Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489:155-9.
104. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.
105. 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;117:563-74.
106. Burger JA, Ghia P, Rosenwald A, et al. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-75.
107. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-84.
108. Duhren-von Minden M, Ubelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489:309-12.
109. Bichi R, Shinton SA, Martin ES, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci U S A. 2002;99:6955-60.
110. Wiestner A. Emerging role of kinase targeted strategies in chronic lymphocytic leukemia. Blood. 2012.
111. 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.
112. Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 2008;111:2230-7.
113. 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.
114. 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.
115. 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;26:1576-83.
116. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075-80.
117. 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.
118. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182-9.
119. O'Brien S, Burger J, Blum KA, et al. The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): follow-up of a phase Ib/II study. Blood. 2011;118:983a.
120. Ramadani F, Bolland DJ, Garcon F, et al. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal. 2010;3:ra60.
121. Jou ST, Carpino N, Takahashi Y, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22:8580-91.
122. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591-4.
123. 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.
124. 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.
125. Coutre S, Byrd JC, Furman RR, et al. Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2011;29:6631a.