The JAK2 exon 12 mutations: A comprehensive review

American Journal of Hematology

Volumn 86, Issue 8, 2011, Pages 668-676

  Scott, Linda M ^a,b  

^a UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^b University of Texas Health Science Center at San Antonio   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BCR ABL PROTEIN; DNA; ERYTHROPOIETIN; HEMOGLOBIN; JANUS KINASE 2; RNA;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; BUDD CHIARI SYNDROME; CHRONIC MYELOID LEUKEMIA; CLINICAL FEATURE; ERYTHROCYTOSIS; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; EXON; GAIN OF FUNCTION MUTATION; GENE DELETION; GENE DUPLICATION; GENE MUTATION; GENETIC VARIABILITY; GRANULOCYTE; HEMATOCRIT; HORMONE BLOOD LEVEL; HUMAN; LARGE CELL LYMPHOMA; LEUKOCYTE; MUTATIONAL ANALYSIS; MYELODYSPLASTIC SYNDROME; MYELOPROLIFERATIVE DISORDER; NONHUMAN; PHENOTYPE; POLYCYTHEMIA VERA; PRIORITY JOURNAL; PROTEIN DOMAIN; REFRACTORY ANEMIA WITH RINGED SIDEROBLASTS; RETROVIRUS; REVIEW; SEQUENCE ALIGNMENT; SINGLE NUCLEOTIDE POLYMORPHISM; THROMBOCYTE; THROMBOCYTOSIS; TRANSGENIC ANIMAL; VEIN THROMBOSIS;

AMINO ACID SEQUENCE; ANIMALS; DIAGNOSIS, DIFFERENTIAL; ERYTHROPOIESIS; EXONS; HUMANS; JANUS KINASE 2; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MUTATION; POLYCYTHEMIA VERA; PROTEIN STRUCTURE, TERTIARY; SEQUENCE ALIGNMENT;

EID: 79960347715     PISSN: 03618609     EISSN: 10968652     Source Type: Journal    
DOI: 10.1002/ajh.22063     Document Type: Review

References (99)

1. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-1061.
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: 1144-1148.
3. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779-1790.
4. 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: 387-397.
5. Pardanani A, Vannucchi AM, Passamonti F, et al. JAK inhibitor therapy for myelofibrosis: Critical assessment of value and limitations. Leukemia 2011; 25: 218-225.
6. 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: 1117-1127.
7. Pardanani A, Hood J, Lasho T, et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658-1668.
8. 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: 5663-5671.
9. Dawson MA, Curry JE, Barber K, et al. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. Br J Haematol 2010; 150: 46-57.
10. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459-468.
11. 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.
12. Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 2010; 116: 988-992.
13. Scott LM, Campbell PJ, Baxter EJ, et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood 2005; 106: 2920-2921.
14. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162-2168.
15. Verstovsek S, Silver RT, Cross NC, Tefferi A. JAK2V617F mutational frequency in polycythemia vera: 100%, >90%, less? Leukemia 2006; 20: 2067.
16. Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. N Engl J Med 1974; 290: 1382.
17. Scott LM, Scott MA, Campbell PJ, Green AR. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood 2006; 108: 2435-2437.
18. Bench AJ, Nacheva EP, Champion KM, Green AR. Molecular genetics and cytogenetics of myeloproliferative disorders. Baillieres Clin Haematol 1998; 11: 819-848.
19. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290-293.
20. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984; 36: 93-99.
21. Morris CM, Reeve AE, Fitzgerald PH, et al. Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia. Nature 1986; 320: 281-283.
22. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002; 107: 76-94.
23. Demiroglu A, Steer EJ, Heath C, et al. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: Transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 2001; 98: 3778-3783.
24. Baxter EJ, Hochhaus A, Bolufer P, et al. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet 2002; 11: 1391-1397.
25. Papadopoulos P, Ridge SA, Boucher CA, et al. The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res 1995; 55: 34-38.
26. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007; 21: 1960-1963.
27. Colaizzo D, Amitrano L, Tiscia GL, et al. A new JAK2 gene mutation in patients with polycythemia vera and splanchnic vein thrombosis. Blood 2007; 110: 2768-2769.
28. Williams DM, Kim AH, Rogers O, et al. Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol 2007; 35: 1641-1646.
29. Percy MJ, Scott LM, Erber WN, et al. The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica 2007; 92: 1607-1614.
30. Martinez-Aviles L, Besses C, Alvarez-Larran A, et al. JAK2 exon 12 mutations in polycythemia vera or idiopathic erythrocytosis. Haematologica 2007; 92: 1717-1718.
31. Butcher CM, Hahn U, To LB, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia 2008; 22: 870-873.
32. Pietra D, Li S, Brisci A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111: 1686-1689.
33. Li S, Kralovics R, De Libero G, et al. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 2008; 111: 3863-3866.
34. Ormazabal C, Hurtado C, Aranaz P, et al. Low frequency of JAK2 exon 12 mutations in classic and atypical CMPDs. Leuk Res 2008; 32: 1485-1487.
35. Rothlisberger B, Huber A, Bargetzi M, et al. JAK2 exon 12 mutation in JAK2V617F-negative polycythemia vera. Leuk Lymphoma 2008; 49: 586-588.
36. Wang YL, Vandris K, Jones A, et al. JAK2 Mutations are present in all cases of polycythemia vera. Leukemia 2008; 22: 1289.
37. Kouroupi E, Zoi K, Parquet N, et al. Mutations in exon 12 of JAK2 are mainly found in JAK2 V617F-negative polycythaemia vera patients. Br J Haematol 2008; 142: 676-679.
38. Cario H, Schwarz K, Herter JM, et al. Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera. Br J Haematol 2008; 142: 622-626.
39. Albiero E, Madeo D, Ruggeri M, et al. Loss of the JAK2 intramolecular auto-inhibition mechanism is predicted by structural modelling of a novel exon 12 insertion mutation in a case of idiopathic erythrocytosis. Br J Haematol 2008; 142: 986-990.
40. Ma W, Kantarjian H, Zhang X, et al. Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias. J Mol Diagn 2009; 11: 49-53.
41. Bernardi M, Ruggeri M, Albiero E, et al. Isolated erythrocytosis in V617F negative patients with JAK2 exon 12 mutations: report of a new mutation. Am J Hematol 2009; 84: 258-260.
42. Schnittger S, Bacher U, Haferlach C, et al. Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera. Haematologica 2009; 94: 414-418.
43. Burjanivova T, Marcinek J, Lasabova Z, et al. A novel JAK2 exon 12 mutation identified in the retrospective analysis of paraffin-embedded tissues of polycythemia vera patients. Diagn Mol Pathol 2009; 18: 108-111.
44. Ohyashiki JH, Hisatomi H, Shimizu S, et al. Detection of low allele burden of JAK2 exon 12 mutations using TA-cloning in patients with erythrocytosis. Jpn J Clin Oncol 2009; 39: 509-513.
45. Kambas K, Mitroulis I, Kourtzelis I, et al. Fast and reliable mutation detection of the complete exon 11-15 JAK2 coding region using non-isotopic RNase cleavage assay (NIRCA). Eur J Haematol 2009; 83: 215-219.
46. Siemiatkowska A, Bieniaszewska M, Hellmann A, Limon J. JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms. Leuk Res 2010; 34: 387-389.
47. Beer PA, Jones AV, Bench AJ, et al. Clonal diversity in the myeloproliferative neoplasms: independent origins of genetically distinct clones. Br J Haematol 2009; 144: 904-908.
48. Ugo V, Tondeur S, Menot ML, et al. Interlaboratory development and validation of a HRM method applied to the detection of JAK2 exon 12 mutations in polycythemia vera patients. PLoS One 2010; 5: e8893.
49. Lakey MA, Pardanani A, Hoyer JD, et al. Bone marrow morphologic features in polycythemia vera with JAK2 exon 12 mutations. Am J Clin Pathol 2010; 133: 942-948.
50. Yeh YM, Chen YL, Cheng HY, et al. High percentage of JAK2 exon 12 mutation in Asian patients with polycythemia vera. Am J Clin Pathol 2010; 134: 266-270.
51. Zhang SJ, Qiu HX, Li JY, et al. The analysis of JAK2 and MPL mutations and JAK2 single nucleotide polymorphisms in MPN patients by MassARRAY assay. Int J Lab Hematol 2010; 32: 381-386.
52. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289-2301.
53. Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23: 2183-2186.
54. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42: 722-726.
55. Theocharides A, Passweg JR, Medinger M, et al. The allele burden of JAK2 mutations remains stable over several years in patients with myeloproliferative disorders. Haematologica 2008; 93: 1890-1893.
56. Wilkins BS, Erber WN, Bareford D, et al. Bone marrow pathology in essential thrombocythemia: Interobserver reliability and utility for identifying disease subtypes. Blood 2008; 111: 60-70.
57. Dupont S, Masse A, James C, et al. The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood 2007; 110: 1013-1021.
58. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366: 1945-1953.
59. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011; 117: 2813-2816.
60. Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010; 24: 1574-1579.
61. Hasle H, Wadsworth LD, Massing BG, et al. A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada. Br J Haematol 1999; 106: 1027-1032.
62. WHO classification of the chronic myeloproliferative diseases (CMPD): polycythemia vera, chronic idiopathic myelofibrosis, essential thrombocythemia and CMPD unclassifiable. In: Jaffe SS, Harris NL, Sterm A, Vardiman JW, editors. WHO Classification of Tumours: Tumours of Haematopoiesis and Lymphoid Tissues. Lyon, France: ARC Press; 2001. pp 31-42.
63. Pearson TC. Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol 2001; 38: 21-24.
64. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 2007; 110: 1092-1097.
65. Jeong EG, Kim SH, Kim MS, et al. Absence of JAK2 exon 12 mutation in acute leukemias. Acta Haematol 2008; 119: 38-39.
66. Inami M, Yamaguchi H, Hasegawa S, et al. Analysis of the exon 12 and 14 mutations of the JAK2 gene in Philadelphia chromosome-positive leukemia. Leukemia 2008; 22: 216.
67. Wu D, Dutra B, Lindeman N, et al. No evidence for the JAK2 (V617F) or JAK2 exon 12 mutations in primary mediastinal large B-cell lymphoma. Diagn Mol Pathol 2009; 18: 144-149.
68. Wardrop D, Steensma DP. Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? Br J Haematol 2009; 144: 809-817.
69. Malcovati L, Della Porta MG, Pietra D, et al. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood 2009; 114: 3538-3545.
70. Patel RK, Lea NC, Heneghan MA, et al. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 2006; 130: 2031-2038.
71. Primignani M, Barosi G, Bergamaschi G, et al. Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis. Hepatology 2006; 44: 1528-1534.
72. Kiladjian JJ, Cervantes F, Leebeek FW, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: A report on 241 cases. Blood 2008; 111: 4922-4929.
73. Bergamaschi GM, Primignani M, Barosi G, et al. MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction. Blood 2008; 111: 4418.
74. Fiorini A, Chiusolo P, Rossi E, et al. Absence of the JAK2 exon 12 mutations in patients with splanchnic venous thrombosis and without overt myeloproliferative neoplasms. Am J Hematol 2009; 84: 126-127.
75. Scott LM, Beer PA, Bench AJ, et al. Prevalance of JAK2 V617F and exon 12 mutations in polycythaemia vera. Br J Haematol 2007; 139: 511-512.
76. 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: 446-449.
77. Olcaydu D, Harutyunyan A, Jager R, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 2009; 41: 450-454.
78. Olcaydu D, Skoda RC, Looser R, et al. The 'GGCC' haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 2009; 23: 1924-1926.
79. Jones AV, Campbell PJ, Beer PA, et al. The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood 2010; 115: 4517-4523.
80. Jones AV, Cross NC, White HE, et al. Rapid identification of JAK2 exon 12 mutations using high resolution melting analysis. Haematologica 2008; 93: 1560-1564.
81. Rapado I, Grande S, Albizua E, et al. High resolution melting analysis for JAK2 exon 14 and exon 12 mutations: A diagnostic tool for myeloproliferative neoplasms. J Mol Diagn 2009; 11: 155-161.
82. Laughlin TS, Moliterno AR, Stein BL, Rothberg PG. Detection of exon 12 mutations in the JAK2 gene: Enhanced analytical sensitivity using clamped PCR and nucleotide sequencing. J Mol Diagn 2010; 12: 278-282.
83. Wilks AF, Harpur AG, Kurban RR, et al. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991; 11: 2057-2065.
84. Saharinen P, Takaluoma K, Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol 2000; 20: 3387-3395.
85. 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.
86. Giordanetto F, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7. Protein Eng 2002; 15: 727-737.
87. Lee TS, Ma W, Zhang X, et al. Structural effects of clinically observed mutations in JAK2 exons 13-15: Comparison with V617F and exon 12 mutations. BMC Struct Biol 2009; 9: 58.
88. Elliott J, Suessmuth Y, Scott LM, et al. SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases. Haematologica 2009; 94: 576-580.
89. Zhao L, Dong H, Zhang CC, et al. A JAK2 interdomain linker relays Epo receptor engagement signals to kinase activation. J Biol Chem 2009; 284: 26988-26998.
90. 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.
91. Zhao R, Follows GA, Beer PA, et al. Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. N Engl J Med 2008; 359: 2778-2789.
92. Schaub FX, Looser R, Li S, et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood 2010; 115: 2003-2007.
93. 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: 1652-1660.
94. 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: 4274-4281.
95. 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.
96. Li S, Hao-Shen H, Tiedt R, Skoda RC. Transgenic mice expressing a JAK2 exon 12 mutation display isolated erythrocytosis closely resembling the human JAK2 exon 12 polycythemia. In: The 15th Congress of the European Hematology Association, Barcelona, Spain; 2010.
97. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 2008; 111: 3931-3940.
98. Bercovich D, Ganmore I, Scott LM, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372: 1484-1492.
99. Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2009; 106: 9414-9418.