Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Ferrajoli A, Faderl S, Ravandi F, Estrov Z: The JAK-STAT pathway: a therapeutic target in hematological malignancies. Curr Cancer Drug Targets 2006,6(8):671–679. 10.2174/156800906779010227

Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN: Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity 1999,11(2):225–230. 10.1016/S1074-7613(00)80097-7

Friedrich K, Kammer W, Erhardt I, Brandlein S, Sebald W, Moriggl R: Activation of STAT5 by IL-4 relies on Janus kinase function but not on receptor tyrosine phosphorylation, and can contribute to both cell proliferation and gene regulation. Int Immunol 1999,11(8):1283–1294. 10.1093/intimm/11.8.1283

Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, et al.: Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 1999,10(2):249–259. 10.1016/S1074-7613(00)80025-4

Bradley HL, Hawley TS, Bunting KD: Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells. Blood 2002,100(12):3983–3989. 10.1182/blood-2002-05-1602

Bunting KD, Bradley HL, Hawley TS, Moriggl R, Sorrentino BP, Ihle JN: Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood 2002,99(2):479–487. 10.1182/blood.V99.2.479

Ward AC, Touw I, Yoshimura A: The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 2000,95(1):19–29.

Wells JA, de Vos AM: Hematopoietic receptor complexes. Annu Rev Biochem 1996, 65: 609–634. 10.1146/annurev.bi.65.070196.003141

Carter-Su C, Smit LS: Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent Prog Horm Res 1998, 53: 61–82. discussion 82–63

Valentino L, Pierre J: JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 2006,71(6):713–721. 10.1016/j.bcp.2005.12.017

Vera J, Rateitschak K, Lange F, Kossow C, Wolkenhauer O, Jaster R: Systems biology of JAK-STAT signalling in human malignancies. Prog Biophys Mol Biol 2011,106(2):426–434. 10.1016/j.pbiomolbio.2011.06.013

Levy DE, Darnell JE Jr: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002,3(9):651–662.

Shuai K, Liu B: Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003,3(11):900–911. 10.1038/nri1226

Shuai K, Liu B: Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 2005,5(8):593–605. 10.1038/nri1667

Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K: Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997,278(5344):1803–1805. 10.1126/science.278.5344.1803

Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K: Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A 1998,95(18):10626–10631. 10.1073/pnas.95.18.10626

Arora T, Liu B, He H, Kim J, Murphy TL, Murphy KM, Modlin RL, Shuai K: PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem 2003,278(24):21327–21330. 10.1074/jbc.C300119200

Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A: Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 2011,31(5):980–985. 10.1161/ATVBAHA.110.207464

Rawlings JS, Rosler KM, Harrison DA: The JAK/STAT signaling pathway. J Cell Sci 2004,117(Pt 8):1281–1283.

Benekli M, Baumann H, Wetzler M: Targeting signal transducer and activator of transcription signaling pathway in leukemias. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2009,27(26):4422–4432. 10.1200/JCO.2008.21.3264

James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005,434(7037):1144–1148. 10.1038/nature03546

Levine RL, Gilliland DG: Myeloproliferative disorders. Blood 2008,112(6):2190–2198. 10.1182/blood-2008-03-077966

Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, et al.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005,365(9464):1054–1061.

Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Eng J Med 2005,352(17):1779–1790. 10.1056/NEJMoa051113

Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, et al.: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005,7(4):387–397. 10.1016/j.ccr.2005.03.023

Tefferi A, Lasho TL, Patnaik MM, Finke CM, Hussein K, Hogan WJ, Elliott MA, Litzow MR, Hanson CA, Pardanani A: JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2010,24(1):105–109. 10.1038/leu.2009.225

Passamonti F, Rumi E: Clinical relevance of JAK2 (V617F) mutant allele burden. Haematologica 2009,94(1):7–10. 10.3324/haematol.2008.001271

Spivak JL, Silver RT: The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood 2008,112(2):231–239. 10.1182/blood-2007-12-128454

Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Eng J Med 2007,356(5):459–468. 10.1056/NEJMoa065202

Teofili L, Martini M, Cenci T, Petrucci G, Torti L, Storti S, Guidi F, Leone G, Larocca LM: Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation. Blood 2007,110(1):354–359. 10.1182/blood-2007-01-069237

Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B, Delsol G, Laurent G, Dastugue N, Brousset P: The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 2005,24(48):7248–7252. 10.1038/sj.onc.1208850

Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R, Pies A, Wormann B, Haase D, Bohlander SK: A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes Chromosomes Cancer 2005,44(3):329–333. 10.1002/gcc.20235

Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, et al.: Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 1997,90(7):2535–2540.

Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, et al.: Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 2008,205(4):751–758. 10.1084/jem.20072182

Murati A, Gelsi-Boyer V, Adelaide J, Perot C, Talmant P, Giraudier S, Lode L, Letessier A, Delaval B, Brunel V, et al.: PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2005,19(9):1692–1696. 10.1038/sj.leu.2403879

Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, et al.: The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005,65(7):2662–2667. 10.1158/0008-5472.CAN-04-4263

Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, et al.: A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997,278(5341):1309–1312. 10.1126/science.278.5341.1309

Ratner L: JAK blockade and HTLV. Blood 2011,117(6):1771–1772. 10.1182/blood-2010-12-322008

Schade AE, Wlodarski MW, Maciejewski JP: Pathophysiology defined by altered signal transduction pathways: the role of JAK-STAT and PI3K signaling in leukemic large granular lymphocytes. Cell Cycle 2006,5(22):2571–2574. 10.4161/cc.5.22.3449

Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P, Pileri SA, Reiter A, Dirnhofer S, Tzankov A: Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 2009,22(3):476–487. 10.1038/modpathol.2008.207

Zhang Q, Nowak I, Vonderheid EC, Rook AH, Kadin ME, Nowell PC, Shaw LM, Wasik MA: Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. Proc Natl Acad Sci U S A 1996,93(17):9148–9153. 10.1073/pnas.93.17.9148

Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M, Bateman CM, Anderson K, Chaplin T, Young BD, et al.: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 2009,113(3):646–648. 10.1182/blood-2008-08-170928

Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K, Macintyre EA, Villeval JL, Vainchenker W, Berger R, et al.: Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Blood 2007,109(5):2202–2204. 10.1182/blood-2006-09-045963

Poitras JL, Dal Cin P, Aster JC, Deangelo DJ, Morton CC: Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. Genes Chromosomes Cancer 2008,47(10):884–889. 10.1002/gcc.20585

Frank DA, Mahajan S, Ritz J: B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest 1997,100(12):3140–3148. 10.1172/JCI119869

Melzner I, Bucur AJ, Bruderlein S, Dorsch K, Hasel C, Barth TF, Leithauser F, Moller P: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 2005,105(6):2535–2542. 10.1182/blood-2004-09-3701

Van Roosbroeck K, Cox L, Tousseyn T, Lahortiga I, Gielen O, Cauwelier B, De Paepe P, Verhoef G, Marynen P, Vandenberghe P, et al.: JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma. Blood 2011,117(15):4056–4064. 10.1182/blood-2010-06-291310

Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, Mattfeldt T, Barth TF, Moller P: Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 2006,25(18):2679–2684. 10.1038/sj.onc.1209151

Ghoshal Gupta S, Baumann H, Wetzler M: Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia. Leuk Res 2008,32(7):1005–1014. 10.1016/j.leukres.2007.11.035

Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL, DeWald GW, Kaufmann SH: JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2006,20(6):971–978. 10.1038/sj.leu.2404206

Maurer AB, Wichmann C, Gross A, Kunkel H, Heinzel T, Ruthardt M, Groner B, Grez M: The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complex. Blood 2002,99(8):2647–2652. 10.1182/blood.V99.8.2647

Constantinescu SN, Girardot M, Pecquet C: Mining for JAK-STAT mutations in cancer. Trends Biochem Sci 2008,33(3):122–131. 10.1016/j.tibs.2007.12.002

Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, Berger R, Clark JJ, Willis SG, Nguyen KT, et al.: The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005,106(10):3377–3379. 10.1182/blood-2005-05-1898

Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, Sekeres MA, Maciejewski JP: Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 2006,108(7):2173–2181. 10.1182/blood-2006-02-005751

Zl W, Yq S, Yf S, Zhu J: High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J Hematol Oncol 2011,4(1):31. 10.1186/1756-8722-4-31

Quintanilla-Martinez L, Kremer M, Specht K, Calzada-Wack J, Nathrath M, Schaich R, Hofler H, Fend F: Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events. Am J Pathol 2003,162(5):1449–1461. 10.1016/S0002-9440(10)64278-2

Zhao A, Gao R, Zhao Z: Development of a highly sensitive method for detection of JAK2V617F. J Hematol Oncol 2011,4(1):40. 10.1186/1756-8722-4-40

Tognon R, Gasparotto E, Neves R, Nunes N, Ferreira A, Palma P, Kashima S, Covas D, Santana M, Souto E, et al.: Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis. J Hematol Oncol 2012,5(1):2. 10.1186/1756-8722-5-2

Zhao W, Du Y, Ho W, Fu X, Zhao Z: JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell lines. Experimental Hematology & Oncology 2012,1(1):15. 10.1186/2162-3619-1-15

Passamonti F, Maffioli M, Caramazza D: New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol 2012,19(2):117–123. 10.1097/MOH.0b013e32834ff575

Randhawa J, Ostojic A, Vrhovac R, Atallah E, Verstovsek S: Splenomegaly in myelofibrosis–new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors. J Hematol Oncol 2012,5(1):43. 10.1186/1756-8722-5-43

Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, Estrov Z, Fridman JS, Bradley EC, Erickson-Viitanen S, et al.: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Eng J Med 2010,363(12):1117–1127. 10.1056/NEJMoa1002028

Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Eng J Med 2011,365(15):1455–1457. 10.1056/NEJMc1109555

Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T, Pierce S, Jabbour E, Borthakur G, Rumi E, et al.: Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012,120(6):1202–1209. 10.1182/blood-2012-02-414631

Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, Faderl S, Ferrajoli A, Borthakur G, George S, et al.: Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012,119(20):4614–4618. 10.1182/blood-2011-12-400051

Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, et al.: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Eng J Med 2012,366(9):787–798. 10.1056/NEJMoa1110556

Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, et al.: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Eng J Med 2012,366(9):799–807. 10.1056/NEJMoa1110557

Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J, et al.: Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008,13(4):311–320. 10.1016/j.ccr.2008.02.009

Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A: TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2008,22(9):1790–1792. 10.1038/leu.2008.56

Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A: Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011,29(7):789–796. 10.1200/JCO.2010.32.8021

Santos FP, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, Kennedy D, Estrov Z, Cortes J, Verstovsek S: Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2010,115(6):1131–1136. 10.1182/blood-2009-10-246363

Moliterno AR, Hexner E, Roboz GJ, Carroll M, Luger S, Mascarenhas J, Hoffman R, Bensen-Kennedy DM: An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive PV and ET: Update of 39 Enrolled Patients. ASH Annual Meeting Abstracts 2009,114(22):753.

Sparidans RW, Durmus S, Xu N, Schinkel AH, Schellens JH, Beijnen JH: Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2012, 895–896: 174–177.

Monaghan KA, Khong T, Burns CJ, Spencer A: The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2011,25(12):1891–1899. 10.1038/leu.2011.175

Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, Druker BJ, Burns CJ, Fantino E, Deininger MW: CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood 2010,115(25):5232–5240. 10.1182/blood-2009-05-223727

Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A: CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2009,23(8):1441–1445. 10.1038/leu.2009.50

Pardanani A, Gotlib J, Gupta V, Roberts AW, Wadleigh M, Sirhan S, Litzow MR, Hogan WJ, Begna K, Smith G, et al.: An Expanded Multicenter Phase I/II Study of CYT387, a JAK- 1/2 Inhibitor for the Treatment of Myelofibrosis. ASH Annual Meeting Abstracts 2011,118(21):3849.

Pardanani AD, Caramazza D, George G, Lasho TL, Hogan WJ, Litzow MR, Begna K, Hanson CA, McClure RF, Bavisotto LM, et al.: Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. ASCO Meeting Abstracts 2011,29(15_suppl):6514.

Hart S, Goh KC, Novotny-Diermayr V, Tan YC, Madan B, Amalini C, Ong LC, Kheng B, Cheong A, Zhou J, et al.: Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood cancer journal 2011,1(11):e44. 10.1038/bcj.2011.43

Poulsen A, William A, Blanchard S, Lee A, Nagaraj H, Wang H, Teo E, Tan E, Goh KC, Dymock B: Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). J Comput Aided Mol Des 2012,26(4):437–450. 10.1007/s10822-012-9572-z

Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, Madan B, Amalini C, Loh YK, Ong LC, et al.: SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2011,25(11):1751–1759. 10.1038/leu.2011.148

William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, et al.: Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem 2011,54(13):4638–4658. 10.1021/jm200326p

Komrokji RS, Wadleigh M, Seymour JF, Roberts AW, To LB, Zhu HJ, Mesa RA: Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. ASH Annual Meeting Abstracts 2011,118(21):282.

Younes A, Fanale MA, McLaughlin P, Copeland A, Zhu J, de Castro Faria S: Phase I Study of a Novel Oral JAK-2 Inhibitor SB1518 In Patients with Relapsed Lymphoma: Evidence of Clinical and Biologic Activity In Multiple Lymphoma Subtypes. ASH Annual Meeting Abstracts 2010,116(21):2830.

Verstovsek S, Mesa RA, Rhoades SK, Giles JLK, Pitou C, Jones E, Walgren RA, Prchal JT: Phase I Study of the JAK2 V617F Inhibitor, LY2784544, in Patients with Myelofibrosis (MF), Polycythemia Vera (PV), and Essential Thrombocythemia (ET). ASH Annual Meeting Abstracts 2011,118(21):2814.

Shah NP, Olszynski P, Sokol L, Verstovsek S, Hoffman R, List AF, Cortes J, Kantarjian HM, Gilliland DG, Clary DO, et al.: A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis. ASH Annual Meeting Abstracts 2008,112(11):98.

Paquette R, Sokol L, Shah NP, Silver RT, List AF, Clary DO, Bui LA, Talpaz M: A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Polycythemia Vera. ASH Annual Meeting Abstracts 2008,112(11):2810.

Tefferi A: JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Blood 2012,119(12):2721–2730. 10.1182/blood-2011-11-395228

Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K, Kotera T, Shibayama H, Hori K, et al.: Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood cancer journal 2011,1(7):e29. 10.1038/bcj.2011.29

Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, et al.: Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2012,26(2):280–288. 10.1038/leu.2011.292

Scuto A, Krejci P, Popplewell L, Wu J, Wang Y, Kujawski M, Kowolik C, Xin H, Chen L, Wang Y, et al.: The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2011,25(3):538–550. 10.1038/leu.2010.289

Derenzini E, Lemoine M, Buglio D, Katayama H, Ji Y, Davis RE, Sen S, Younes A: The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood cancer journal 2011,1(12):e46. 10.1038/bcj.2011.46

Loveless ME, Lawson D, Collins M, Nadella MV, Reimer C, Huszar D, Halliday J, Waterton JC, Gore JC, Yankeelov TE: Comparisons of the efficacy of a Jak1/2 inhibitor (AZD1480) with a VEGF signaling inhibitor (cediranib) and sham treatments in mouse tumors using DCE-MRI, DW-MRI, and histology. Neoplasia 2012,14(1):54–64.

McFarland BC, Ma JY, Langford CP, Gillespie GY, Yu H, Zheng Y, Nozell SE, Huszar D, Benveniste EN: Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol Cancer Ther 2011,10(12):2384–2393. 10.1158/1535-7163.MCT-11-0480

Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, Sattler M: Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2012,26(4):708–715. 10.1038/leu.2011.255

Xin H, Herrmann A, Reckamp K, Zhang W, Pal S, Hedvat M, Zhang C, Liang W, Scuto A, Weng S, et al.: Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res 2011,71(21):6601–6610. 10.1158/0008-5472.CAN-11-1217

Mankan AK, Greten FR: Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitors. Expert Opin Investig Drugs 2011,20(9):1263–1275. 10.1517/13543784.2011.601739

Ioannidis S, Lamb ML, Wang T, Almeida L, Block MH, Davies AM, Peng B, Su M, Zhang HJ, Hoffmann E, et al.: Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)p yrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. J Med Chem 2011,54(1):262–276. 10.1021/jm1011319

Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, et al.: The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009,16(6):487–497. 10.1016/j.ccr.2009.10.015

Coppelli FM, Grandis JR: Oligonucleotides as anticancer agents: from the benchside to the clinic and beyond. Curr Pharm Des 2005,11(22):2825–2840. 10.2174/1381612054546752

Jing N, Sha W, Li Y, Xiong W, Tweardy DJ: Rational drug design of G-quartet DNA as anti-cancer agents. Curr Pharm Des 2005,11(22):2841–2854. 10.2174/1381612054546761

Nelson EA, Sharma SV, Settleman J, Frank DA: A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotarget 2011,2(6):518–524.

Perrotti D, Neviani P: Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. Cancer Metastasis Rev 2008,27(2):159–168. 10.1007/s10555-008-9119-x

Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ: Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood 2011,117(21):5701–5709. 10.1182/blood-2010-04-280123

Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, et al.: Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clinical cancer research: an official journal of the American Association for Cancer Research 2011,17(10):3259–3271. 10.1158/1078-0432.CCR-10-3012

Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, Haura E, Sebti S, Hamilton AD, Jove R: Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 2004,3(3):261–269.

Hayakawa F, Sugimoto K, Kurahashi S, Sumida T, Naoe T: A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic Cells. ASH Annual Meeting Abstracts 2011,118(21):577.