PCM1JAK2-fusion: A potential treatment target in myelodysplasticmyeloproliferative and other hemato-lymphoid neoplasms

Expert Opinion on Therapeutic Targets

Volumn 15, Issue 1, 2011, Pages 53-62

  Hoeller, Sylvia ^a   Walz, Christoph ^b   Reiter, Andreas ^b   Dirnhofer, Stephan ^a   Tzankov, Alexandar ^a  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

^b UNIVERSITY OF MANNHEIM   (Germany)

Author keywords

JAK2; JAK2 inhibitors; Myelodysplastic myeloproliferative neoplasm; PCM1JAK2 fusion

Indexed keywords

AZD 1480; CYT 387; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HYBRID PROTEIN; INCB 018424; JANUS KINASE 2; JANUS KINASE INHIBITOR; LESTAURTINIB; MITOGEN ACTIVATED PROTEIN KINASE; PERICENTRIOLAR MATERIAL 1 JANUS KINASE 2 FUSION PROTEIN; PLATELET DERIVED GROWTH FACTOR RECEPTOR; SB 1518; STAT3 PROTEIN; TG 101348; UNCLASSIFIED DRUG; XL 019; ANTINEOPLASTIC AGENT; AUTOANTIGEN; CELL CYCLE PROTEIN; JAK2 PROTEIN, HUMAN; PCM1 PROTEIN, HUMAN;

B CELL LYMPHOMA; CLINICAL TRIAL; DRUG TARGETING; ENZYME ACTIVATION; EOSINOPHILIA; GENE MUTATION; GENETIC VARIABILITY; HEMATO LYMPHOID NEOPLASM; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MIXED MYELODYSPLASTIC MYELOPROLIFERATIVE DISEASE; MYELOFIBROSIS; OLIGOMERIZATION; ONCOGENE; POINT MUTATION; PROTEIN BINDING; PROTEIN PHOSPHORYLATION; REVIEW; BLOOD DISEASE; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG EFFECT; GENE TRANSLOCATION; GENETICS; MALE; METABOLISM; PATHOPHYSIOLOGY;

ANTINEOPLASTIC AGENTS; AUTOANTIGENS; CELL CYCLE PROTEINS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HEMATOLOGIC NEOPLASMS; HUMANS; JANUS KINASE 2; MALE; MYELODYSPLASTIC-MYELOPROLIFERATIVE DISEASES; POINT MUTATION; TRANSLOCATION, GENETIC;

EID: 78650184331     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.2011.538683     Document Type: Review

References (80)

1. Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene 2000;19:5548-57
2. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172-87
3. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005;5:172-83
4. Goldman JM, Melo JV. Chronic myeloid leukemia - advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451-64
5. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 2010;456:111-27
6. 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)
7. 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
8. Bennett M, Stroncek DF. Recent advances in the bcr-abl negative chronic myeloproliferative diseases. J Transl Med 2006;11:41 A review on the mechanisms of JAK2 activation by point mutations.
9. Schafer AI. Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood 2006;107:4214-22
10. Michiels JJ. Clinical, pathological and molecular features of the chronic myeloproliferative disorders: MPD 2005 and beyond. Hematology 2005;l 1:215-23
11. Kilpivaara O, Levine RL. JAK2 and MPL mutations in myeloproliferative neoplasms: Discovery and science. Leukemia 2008;22:1813-17
12. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004;117:1281-3 . A very comprehensive review of the general principles of the JAK/STAT pathway and its functions.
13. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009:636-642
14. Ziemiecki A, Harpur AG, Wilks AF. JAK protein tyrosine kinases: Their role in cytokine signalling. Trends Cell Biol 1994;4:207-12
15. Radtke S, Haan S, Jorissen A, et al. The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression. J Biol Chem 2005;280:25760-8
16. Khwaja A. The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol 2006;134:366-84
17. Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Ann NY Acad Sci 2009;1171:59-76
18. Kota J, Caceres N, Constantinescu SN. Aberrant signal transduction pathways in myeloproliferative neoplasms. Leukemia 2008;22:1828-40 . An excellent review of signal transduction pathways in myeloproliferative neoplasms.
19. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 2008;19:385-93
20. Baxter EJ, Scott LM, Campbell PJ, et al. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-61
21. James C, Ugo V, Le Couedic JP, et al. Unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144-8 (Pubitemid 40663494)
22. 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
23. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162-8
24. Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: It all makes sense. Blood 2005;105:4187-90
25. 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
26. Tefferi A. JAK and MPL mutations in myeloid malignancies. Leuk Lymphoma 2008;49:388-97
27. Malinge S, Ben-Abdelali R, Settegrana C, et al. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Blood 2007;109:2202-4
28. Bercovich D, Ganmore I, Scott LM, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008;372:1484-92
29. Heiss S, Erdel M, Gunsilius E, et al. Myelodysplastic/myeloproliferative disease with erythropoietic hyperplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24): First description of a case. Hum Pathol 2005;36:1148-51 The first description, to our knowledge, of the t(8;9) translocation in a myelodysplastic/ myeloproliferative disease.
30. Vu HA, Xinh PT, Masuda M, et al. FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13; q12) translocation. Leukemia 2006;20:1414-21
31. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201-14
32. Golub TR, Barker GF, Lovett M, et al. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77:307-16
33. Tzankov A, Sotlar K, Muhlematter D, et al. Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with (13;13)(q12;q22) involving FLT3. J Clin Pathol 2008;61:958-61
34. Litzow M. More flitting about FLT3. Blood 2005;106:3331-2
35. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708-10
36. 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
37. Peeters P, Raynaud SD, Cools J, et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptorassociated 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
38. Nguyen MH, Ho JM, Beattie BK, et al. TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3'-kinase/protein kinase B signalling pathway. J Biol Chem 2001;276:32704-13
39. Santos SC, Monni R, Bouchaert I, et al. Involvement of the NF-kB pathway in the transforming properties of the TEL-Jak2 leukemogenic fusion protein. FEBS Lett 2001;497:148-52
40. Malinge S, Monni R, Bernard O, et al. Activation of the NF-kB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKalpha. Oncogene 2006;25:3589-97
41. Reiter A, Walz C, Watmore A, 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;65:2662-7
42. Bousquet M, Quelen C, De Mas V, et al. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 2005;24:7248-52
43. Murati A, Gelsi-Boyer V, Adelaide J, et al. PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia 2005;19:1692-6
44. Mark HF, Sotomayor EA, Nelson M, et al. Chronic idiopathic myelofibrosis (CIMF) resulting from a unique 3;9 translocation disrupting the janus kinase 2 (JAK2) gene. Exp Mol Pathol 2006;81:217-23
45. Balczon R, Bao L, Zimmer WE. PCM-1, A 228-kD centrosome autoantigen with a distinct cell cycle distribution. J Cell Biol 1994;124:783-93
46. Dammermann A, Merdes A. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. J Cell Biol 2002;159:255-66
47. Balczon R, Simerly C, Takahashi D, et al. Arrest of cell cycle progression during first interphase in murine zygotes microinjected with anti-PCM-1 antibodies. Cell Motil Cytoskeleton 2002;52:183-92
48. Adelaide J, Perot C, Gelsi-Boyer V, et al. A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma. Leukemia 2006;20:536-7
49. Huang KP, Chase AJ, Cross NC, et al. Evolutional change of karyotype with t (8;9)(p22;p24) and HLA-DR immunophenotype in relapsed acute myeloid leukemia. Int J Hematol 2008;88:197-201
50. Bacher U, Reiter A, Haferlach T, et al. A combination of cytomorphology, cytogenetic analysis, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction for establishing clonality in cases of persisting hypereosinophilia. Haematologica 2006;91:817-20
51. Meier C, Hoeller S, Bourgau C, et al. Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol 2009;22:476-87
52. Van Roosbroeck K, Lahortiga I, Cools J, et al. A novel t(4;9)(q21;p24) fuses SEC13A to JAK2 in nodular sclerosis Hodgkin Lymphoma. Haematologica 2007;92(s5):43
53. Van Roosbroeck K, Cools J, Dierickx D, et al. ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica 2010;95:509-13
54. Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edition. IARC, Lyon; 2008
55. Tzankov A, Heiss S. Myeloproliferative disorders carrying the t(8;9) (PCM1-JAK2) translocation. Hum Pathol 2006;37:500-12
56. Najfeld V, Cozza A, Berkofsy-Fessler W, et al. Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms. Exp Hematol 2007;35:1668-76
57. Poitras JL, Dal Cin P, Aster JC, et al. 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;47:884-9
58. Levy DE, Darnell JE Jr. Stats: Transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002;3:651-62
59. Tzankov A, Meier C, Hirschmann P, et al. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 2008;93:193-200
60. Ritz O, Guiter C, Castellano F, et al. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 2009;114:1236-42
61. Holtick U, Vockerodt M, Pinkert D, et al. STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis. Leukemia 2005;19:936-44
62. Cross NC, Daley GQ, Green AR, et al. BCR-ABL1-positive CML and BCR-ABL1-negative chronic myeloproliferative disorders: Some common and contrasting features. Leukemia 2008;22:1975-89
63. Atallah E, Verstovsek S. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. Expert Rev Anticancer Ther 2009;9:663-70
64. Deal watch. dipping into Incyte's JAK-pot. Nat Rev Drug Discov 2010;9:94
65. Verstovsek S, Passamonti F, Rambaldi A, et al. A Phase 2 studiy of INCB018424, an oral, selective JAK1/JAK2 inhibitor, in patients with advanced polycythemia (PV) and essential thromobcythemia (ET) refractory to hydroxyurea. ASH annual Meeting Abstracts. Blood 2009;114:311
66. Chen AT, Prchal JT. JAK2 kinase inhibitors and myeloproliferative disorders. Curr Opin Hematol 2010;17:110-16
67. Sayyah J, Sayeski PP. Jak2 inhibitors: Rationale and role as therapeutic agents in hematologic malignancies. Curr Oncol Rep 2009;11:117-24
68. Santos FP, Verstovsek S. Developments of novel therapies in myeloproliferative neoplasms. Hematol Educ 2010;4:189-96 A summary of the ongoing clinical trials with JAK inhibitors.
69. Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/ essential thrombocythemia myelofibrosis. Blood 2010;115:1131-6
70. 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
71. Verstovsek S, Kantarjian H, Mesa RA, et al. Long-term follow up and optimized dosing regimen of INCB018424 in patients with myelofibrosis: Durable clinical, functional and symptomatic responses with improved hematological safety. ASH Annual Meeting Abstracts. Blood 2009;114:756
72. Pardanani A, Gotlib J, Jamieson C, et al. TG101348, a JAK2-selective inhibitor, is well tolerated in patients with myelofibrosis and shows substantial therapeutic activity accompained by a reduction in JAK2V617F allele burden. Haematologica 2009;94:abstract 1088
73. Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thrombocythemia/polycythemia vera myelofibrosis. ASH Annual Meeting Abstracts. Blood 2009;114:3905
74. Shah NP, Osszynski P, Sokol L, 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. Blood 2009;112:98
75. Xu RH, Pelicano H, Zhang H, et al. Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia 2005;19:2153-8
76. Johnston PB, Inwards DJ, Colgan JP, et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 2010;85:320-4
77. Moliterno AR, Hexner E, Roboz GJ, et al. 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. Blood 2009;114:753
78. Pardanani A, Gotlib J, Jamieson C, et al. TG101348, a JAK2-selective inhibitor, is well tolerated in patients with myelofibrosis and shows substantial therapeutic activity accompanied by a reduction in JAK2V617F allele burden. Haematologica 2009;94:abstract 1088
79. Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thromobocythemia/polycythemia vera myelofibrosis. ASH Annual Meeting Abstracts. Blood 2009;114:3905
80. Shah NP, Olszynski P, Sokol L, et al. Phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera or post-essential thrombocythemia myelofirosis. ASH Annual Meeting Abstracts. Blood 2008;112:98