Targeting JAK2 in the therapy of myeloproliferative neoplasms

Expert Opinion on Therapeutic Targets

Volumn 16, Issue 3, 2012, Pages 313-324

  Reddy, Mamatha M ^a,b   Deshpande, Anagha ^a,b   Sattler, Martin ^a,b  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

JAK2; Metabolism; Myeloproliferative neoplasms; Signaling; Targeted therapy

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; ALPHA INTERFERON; ANTINEOPLASTIC AGENT; AZD 1480; CORTICOSTEROID; CYT 387; DANAZOL; ERLOTINIB; EVEROLIMUS; GANETESPIB; GIVINOSTAT; HEAT SHOCK PROTEIN 90; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; HYDROXYUREA; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; LESTAURTINIB; LY 2784544; N TERT BUTYL 3 [5 METHYL 2 [4 (4 METHYL 1 PIPERAZINYL)PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; PANOBINOSTAT; PUH 71; RUXOLITINIB; SAR 302503; SB 1518; SB 939; SGI 1776; TG 101348; THALIDOMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VORINOSTAT;

ANTINEOPLASTIC ACTIVITY; CELL GROWTH; CELL METABOLISM; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG TARGETING; ENZYME INHIBITION; GENE MUTATION; HUMAN; HYPERAMYLASEMIA; LEUKEMIA; LYMPHOMA; MALIGNANT TRANSFORMATION; MYELOFIBROSIS; MYELOPROLIFERATIVE DISORDER; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; PROTEIN SYNTHESIS INHIBITION; REVIEW; SIGNAL TRANSDUCTION; SPLENECTOMY; STEM CELL TRANSPLANTATION; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT;

BONE MARROW NEOPLASMS; DRUG RESISTANCE, NEOPLASM; HUMANS; JANUS KINASE 2; MYELOPROLIFERATIVE DISORDERS;

EID: 84858259071     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2012.662956     Document Type: Review

References (96)

1. 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 (Pubitemid 40544655)
2. 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 (Pubitemid 40663494)
3. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-61 (Pubitemid 40386783)
4. 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 (Pubitemid 40570926)
5. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788-92 (Pubitemid 40853184)
6. Levine RL, Gilliland DG. Myeloproliferative disorders. Blood 2008;112:2190-8
7. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 2009;41:446-9
8. Kilpivaara O, Mukherjee S, Schram AM, et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms. Nat Genet 2009;41:455-9
9. Olcaydu D, Harutyunyan A, Jager R, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 2009;41:450-4
10. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer 2010;1:979-93
11. Peeters P, Raynaud SD, Cools J, 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;90:2535-40 (Pubitemid 27413461)
12. Lacronique V, Boureux A, Valle VD, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997;278:1309-12 (Pubitemid 27495745)
13. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;108:3472-6
14. 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
15. Roll JD, Reuther GW. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res 2010;70:7347-52
16. Yamaoka K, Saharinen P, Pesu M, et al. The Janus kinases (Jaks). Genome Biol 2004;5:253
17. Lindauer K, Loerting T, Liedl KR, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng 2001;14:27-37 (Pubitemid 32318935)
18. Saharinen P, Silvennoinen O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J Biol Chem 2002;277:47954-63 (Pubitemid 36159324)
19. Saharinen P, Vihinen M, Silvennoinen O. Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol Biol Cell 2003;14:1448-59 (Pubitemid 36547413)
20. Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell 2001;8:1327-38 (Pubitemid 34085003)
21. Tanner JW, Chen W, Young RL, et al. The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. J Biol Chem 1995;270:6523-30
22. Royer Y, Staerk J, Costuleanu M, et al. Janus kinases affect thrombopoietin receptor cell surface localization and stability. J Biol Chem 2005;280:27251-61 (Pubitemid 41040765)
23. Wernig G, Gonneville JR, Crowley BJ, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood 2008;111:3751-9
24. Zanjani ED, Lutton JD, Hoffman R, Wasserman LR. Erythroid colony formation by polycythemia vera bone marrow in vitro. Dependence on erythropoietin. J Clin Invest 1977;59:841-8 (Pubitemid 8096336)
25. Prchal JF, Axelrad AA. Letter: bone-marrow responses in polycythemia vera. N Engl J Med 1974;290:1382
26. Neubauer H, Cumano A, Muller M, et al. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998;93:397-409 (Pubitemid 28232084)
27. Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998;93:385-95 (Pubitemid 28232083)
28. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9:798-809
29. Onishi M, Nosaka T, Misawa K, et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol 1998;18:3871-9 (Pubitemid 28287910)
30. Teglund S, McKay C, Schuetz E, et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998;93:841-50 (Pubitemid 28257589)
31. Socolovsky M, Fallon AE, Wang S, et al. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/-mice: a direct role for Stat5 in Bcl-XL induction. Cell 1999;98:181-91
32. Lu X, Levine R, Tong W, et al. Expression of a homodimeric type 1 cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci USA 2005;102:18962-7 (Pubitemid 43049549)
33. Funakoshi-Tago M, Tago K, Abe M, et al. STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant. J Biol Chem 2010;285:5296-307
34. Nelson EA, Walker SR, Weisberg E, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 2011;117:3421-9
35. 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
36. Dawson MA, Bannister AJ, Gottgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 2009;461:819-22
37. Sattler M, Griffin JD. JAK2 gets histone H3 rolling. Cancer Cell 2009;16:365-6
38. Rinaldi CR, Rinaldi P, Alagia A, et al. Preferential nuclear accumulation of JAK2V617F in CD34+ but not in granulocytic, megakaryocytic, or erythroid cells of patients with Philadelphia-negative myeloproliferative neoplasia. Blood 2010;116:6023-6
39. Miura O, Nakamura N, Quelle FW, et al. Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Blood 1994;84:1501-7 (Pubitemid 24273018)
40. Shigematsu H, Iwasaki H, Otsuka T, et al. Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity. J Biol Chem 1997;272:14334-40 (Pubitemid 27232848)
41. Jakel H, Weinl C, Hengst L. Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control. Oncogene 2011;30:3502-12
42. Rider L, Shatrova A, Feener EP, et al. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem 2007;282:30985-96 (Pubitemid 350035237)
43. Rui L, Mathews LS, Hotta K, et al. Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Mol Cell Biol 1997;17:6633-44 (Pubitemid 27451210)
44. Liu F, Zhao X, Perna F, et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 2011;19:283-94
45. Laubach JP, Fu P, Jiang X, et al. Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation. Exp Hematol 2009;37:1411-22
46. Grimwade LF, Happerfield L, Tristram C, et al. Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. Br J Haematol 2009;147:495-506
47. Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase I/II study in patients with myelofibrosis. Blood 2011;118:2069-76
48. Fasolo A, Sessa C. Current and future directions in mammalian target of rapamycin inhibitors development. Expert Opin Investig Drugs 2011;20:381-94
49. Lu M, Zhang W, Li Y, et al. Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp Hematol 2010;38:472-80
50. Tefferi A. How i treat myelofibrosis. Blood 2011;117:3494-504
51. 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
52. Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 2010;115:3109-17
53. Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009;16:487-97
54. Pardanani A, Lasho T, Smith G, et al. 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 2009;23:1441-5
55. 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
56. Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008;13:311-20 (Pubitemid 351446195)
57. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011;29:789-96
58. Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: rationale, current data and perspective. Blood Rev 2011;25:229-37
59. George DJ, Dionne CA, Jani J, et al. Sustained in vivo regression of dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res 1999;59:2395-401 (Pubitemid 29242288)
60. Hexner EO, Serdikoff C, Jan M, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 2008;111:5663-71
61. Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002;99:3885-91 (Pubitemid 35332023)
62. Strock CJ, Park JI, Rosen M, et al. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 2003;63:5559-63 (Pubitemid 37139878)
63. William AD, Lee AC, Blanchard S, et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo19.3.1.1(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;54:4638-58
64. Li Z, Xu M, Xing S, et al. Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth. J Biol Chem 2007;282:3428-32 (Pubitemid 47084420)
65. Richter K, Buchner J. Hsp90: chaperoning signal transduction. J Cell Physiol 2001;188:281-90 (Pubitemid 32777169)
66. Gorre ME, Ellwood-Yen K, Chiosis G, et al. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 2002;100:3041-4
67. George P, Bali P, Cohen P, et al. Cotreatment with 17-allylamino- demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res 2004;64:3645-52 (Pubitemid 38657944)
68. Fiskus W, Verstovsek S, Manshouri T, et al. Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells. Clin Cancer Res 2011;17:7347-58
69. Marubayashi S, Koppikar P, Taldone T, et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest 2010;120:3578-93
70. Guerini V, Barbui V, Spinelli O, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F. Leukemia 2008;22:740-7 (Pubitemid 351552623)
71. Wang X, Zhang W, Tripodi J, et al. Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells. Blood 2010;116:5972-82
72. Wang JC, Chen C, Dumlao T, et al. Enhanced histone deacetylase enzyme activity in primary myelofibrosis. Leuk Lymphoma 2008;49:2321-7
73. Kovacs JJ, Murphy PJ, Gaillard S, et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005;18:601-7 (Pubitemid 40726236)
74. Lee J. Clinical efficacy of vorinostat in a patient with essential thrombocytosis and subsequent myelofibrosis. Ann Hematol 2009;88:699-700
75. Finnin MS, Donigian JR, Cohen A, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999;401:188-93 (Pubitemid 29436325)
76. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109-15 (Pubitemid 47218059)
77. Mann BS, Johnson JR, Cohen MH, et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007;12:1247-52 (Pubitemid 350106355)
78. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the histone-deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010;150:446-55
79. Wang Y, Fiskus W, Chong DG, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009;114:5024-33
80. Novotny-Diermayr V, Sausgruber N, Loh YK, et al. Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue. Mol Cancer Ther 2011;10:1207-17
81. Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938-42
82. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876-80 (Pubitemid 32743979)
83. Deshpande A, Reddy MM, Schade GO, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia 2011. Epub ahead of print
84. Hornakova T, Springuel L, Devreux J, et al. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica 2011;96:845-53
85. Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004;127:294-9 (Pubitemid 38962296)
86. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73
87. Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269-70
88. Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010;330:1340-4
89. Reddy MM, Fernandes MS, Deshpande A, et al. The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity. Leukemia 2011. Epub ahead of print
90. Clem B, Telang S, Clem A, et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 2008;7:110-20
91. Rodrigues MS, Reddy MM, Sattler M. Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid Redox Signal 2008;10:1813-48
92. Walz C, Crowley BJ, Hudon HE, et al. Activated Jak2 with the V617F point mutation promotes G1/S phase transition. J Biol Chem 2006;281:18177-83 (Pubitemid 44035617)
93. Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005;105:4163-9 (Pubitemid 40720758)
94. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009;8:579-91
95. Reddy MM, Fernandes MS, Salgia R, et al. NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases. Leukemia 2011;25:281-9
96. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011;118:1723-35