Rola kinaz JAK w patogenezie nowotworów mieloproliferacyjnych Philadelphia-ujemnych. Możliwości terapii celowanej Artykuł przeglądowy
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nowotwory mieloproliferacyjne Philadelphia-ujemne, JAK2, mutacje, inhibitory JAK2
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Abstrakt
W ostatnich latach dokonał się istotny postęp w zrozumieniu patogenezy nowotworów mieloproliferacyjnych, w szczególności tych z mutacjami w obrębie genu JAK2. W 2005 roku liczne grupy badawcze potwierdziły występowanie mutacji V617F w obrębie egzonu 14. genu JAK2. Okazało się, że defekt ten jest obecny u 96% chorych z czerwienicą prawdziwą (PV), u 35–70% pacjentów z nadpłytkowością samoistną (ET) oraz u około 50% osób z pierwotną mielofibrozą (PM). W późniejszym okresie udokumentowano także występowanie innych zaburzeń sekwencji genu JAK2 w obrębie egzonów 12.–15., w tym substytucji nukleotydowych, insercji lub delecji oraz defektów insercyjno-delecyjnych. W większości wymienionych defektów badania eksperymentalne potwierdziły, że ich obecność prowadzi do zakłócenia procesu autoinhibicji kinazy JAK2. Konsekwencją biologiczną wymienionych anomalii jest proliferacja komórek obarczonych defektem, niezależnie od obecności cytokin. Odkrycie związku między obecnością mutacji w obrębie genu JAK2 a rozwojem nowotworów mieloproliferacyjnych stało się przesłanką do podjęcia prac zmierzających do opracowania małocząsteczkowych inhibitorów JAK2. Początkowo były to substancje współzawodniczące z substratami kinazy o miejsce wiązania w obrębie domeny katalitycznej JAK2. Wkrótce potem niezależnej ocenie poddano substancje o budowie zbliżonej do ATP – analogi pyridonów oraz pyrimidyny. Większość z inhibitorów JAK2 to związki współzawodniczące z ATP o miejsce wiązania w obrębie domeny kinazowej [TG101348 (TargeGen), INCB018424 (ruxolitinib, Incyte), CYT387 (Cytopia), CEP-701 (lestaurtinib, Cephalon), XL019 (Exelixis), SB1518 (S*Bio, według licencji Onyx jako ONX0803) oraz AZD1480 (AstraZeneca)]. Ich zastosowanie u pacjentów z mielofibrozą prowadzi do zmniejszenia objętości śledziony u około połowy z nich, zmniejszenia nasilenia objawów ogólnych, wzrostu tolerancji wysiłku fizycznego oraz poprawy jakości życia. U chorych z PV oraz ET terapia za pomocą inhibitorów JAK2 skutkuje znaczącą poprawą w zakresie parametrów krwi obwodowej oraz wyraźnym zmniejszeniem zapotrzebowania na leczenie upustami krwi. Większość z wymienionych inhibitorów JAK2 jest obecnie oceniana w badaniach klinicznych. Wydaje się jednak, że ich zastosowanie może już w niedalekiej przyszłości zmienić obowiązujące standardy terapii JAK2-dodatnich nowotworów mieloproliferacyjnych.
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Lewandowski K. Rola kinaz JAK w patogenezie nowotworów mieloproliferacyjnych Philadelphia-ujemnych. Możliwości terapii celowanej. OncoReview [Internet]. 30 wrzesień 2011 [cytowane 23 lipiec 2024];1(3(3):171-82. Dostępne na: https://journalsmededu.pl/index.php/OncoReview/article/view/254
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Utwór dostępny jest na licencji Creative Commons Uznanie autorstwa – Użycie niekomercyjne 4.0 Międzynarodowe.
Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
Bibliografia
1. Baxter E.J., Scott L.M., Campbell P.J. et al.: Cancer Genome Project Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-1061.
2. James C., Ugo V., Le Couedic J.P. et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-1148.
3. Ma W., Zhang X., Wang X. et al.: MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagn. Mol. Pathol. 2011; 20: 34-9.
4. Panani A.D.: Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disorders: clinical implications. Cancer Lett. 2007; 255: 12-25.
5. Baxter E.J., Scott L.M., Campbell P.J. et al.: Cancer genome project: acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-1061.
6. Passamonti F., Rumi E., Pietra D. et al.: Relation between JAK2 (V617F) mutation status, granulocyte activation and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 2006; 107: 3676-3682.
7. Lippert E., Boissinot M., Kralovics R. et al.: The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006; 108: 1865-1867.
8. Tefferi A., Lasho T.L., Schwager S.M. et al.: The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 2006; 106: 631-635.
9. Jones A.V., Chase A., Silver R.T. et al.: JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat. Genet. 2009; 41: 446-9.
10. Kilpivaara O., Mukherjee S., Schram A.M. et al.: A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat. Genet. 2009; 41: 455-9.
11. Olcaydu D., Harutyunyan A., Jäger R. et al.: A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat. Genet. 2009; 41: 450-4.
12. Pietra D., Li S., Brisci A., Passamonti F. et al.: Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111: 1686-9.
13. Baker S.J., Rane S.G., Reddy E.P.: Hematopoietic cytokine receptor signaling. Oncogene 2007; 26: 6724-37.
14. Jatiani S.S., Baker S.J., Silverman L.R. et al.: JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders: Approaches for Targeted Therapies. Genes Cancer 2010; 1: 979-993.
15. Funakoshi-Tago M., Tago K., Kasahara T. et al.: Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway. Cell Signal. 2008; 20: 1995-2001.
16. Wilks A.F., Harpur A.G., Kurban R.R. 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.
17. Feng J., Witthuhn B.A., Matsuda T. et al.: Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell Biol. 1997; 17: 2497-501.
18. Liu K.D., Gaffen S.L., Goldsmith M.A. et al.: Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Curr. Biol. 1997; 7: 817-26.
19. Saharinen P., Takaluoma K., Silvennoinen O.: Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell Biol. 2000; 20: 3387-95.
20. Lindauer K., Loerting T., Liedl K.R. et al.: 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.
21. 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.
22. 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.
23. Kralovics R., Passamonti F., Buser A.S. et al.: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 2005; 352: 1779-1790.
24. Peeters P., Raynaud S.D., 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.
25. Lacronique V., Boureux A., Valle V.D. et al.: A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278: 1309-12.
26. 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.
27. 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.
28. Murati A., Gelsi-Boyer V., Adélaďde J. et al.: PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia 2005; 19: 1692-6.
29. Adélaďde J., Pérot 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.
30. Bousquet M., Brousset P.: Myeloproliferative disorders carrying the t(8;9) (PCM1-JAK2) translocation. Hum. Pathol. 2006; 37: 500.
31. Griesinger F., Hennig H., Hillmer F. et al.: 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): 9-33.
32. Lane S.W., Fairbairn D.J., McCarthy C. et al.: Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9;22) (p24;q11.2) leading to BCR-JAK2 fusion. Br. J. Haematol. 2008; 142: 503.
33. Poitras J.L., Dal Cin P., Aster J.C. 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.
34. Levine R.L., 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.
35. Tefferi A., Gilliland D.G.: Oncogenes in myeloproliferative disorders. Cell Cycle 2007; 1(6): 550-66.
36. Lee T.S., Ma W., Zhang X. et al.: Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations. Cancer 2009; 115: 1692-700.
37. Dusa A., Mouton C., Pecquet Ch. et al.: JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors. PLoS ONE 2010; 5: 11157.
38. Lee T.S., Ma W., Zhang Xi et al.: Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations. BMC Structural Biology 2009; 9: 58.
39. 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.
40. Scott L.M., Tong W., Levine R.L. et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 2007; 356: 459-68.
41. Pardanani A., Lasho T.L., Finke C. et al.: Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007; 21: 1960-3.
42. Yeh Y.M., Chen Y.L., Cheng H.Y. et al.: High percentage of JAK2 exon 12 mutation in Asian patients with polycythemia vera. Am. J. Clin. Pathol. 2010; 134: 266-70.
43. Jallades L., Hayette S., Tigaud I. et al.: Emergence of therapy-unrelated CML on a background of BCR-ABL-negative JAK2V617F-positive chronic idiopathic myelofibrosis. Leuk. Res. 2008; 32: 1608-10.
44. Krämer A., Reiter A., Kruth J. et al.: JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. Lancet Oncol. 2007; 8: 658-60.
45. Hussein K., Bock O., Seegers A. et al.: Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation. Blood 2007; 109: 4106-7.
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47. Kiss R., Sayeski P.P., Keser G.M.: Recent developments on JAK2 inhibitors: a patent review. Expert Opin. Ther. Pat. 2010; 20: 471-95.
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50. Mesa R.A., Kantarjian H., Tefferi A. et al.: Evaluating the serial use of the myelofibrosis symptom assessment form for measuring symptomatic improvement: Performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial. Cancer 2011 Apr 8; doi: 10.1002/cncr.26129.
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53. Pardanani A., George G., Lasho T.L. et al.: A Phase I/II study of CYT387, an oral JAK-1/2 Inhibitor, in myelofibrosis: significant response rates in anemia, splenomegaly, and constitutional symptoms. Blood 2010; 116: abstract 460.
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55. William A.D., Lee A.C., Blanchard S. 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)]heptacosa1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/ /FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma. J. Med. Chem. 2011 May 23 [online].
56. Ioannidis S., Lamb M.L., Wang T. et al.: Discovery of 5-chloro-N(2)-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N(4)-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. J. Med. Chem. 2010 Dec 7 [online].
57. Baffert F., Régnier C.H., De Pover A. et al.: Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. Mol. Cancer Ther. 2010; 9: 1945-55.
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60. Kasper S., Breitenbuecher F., Hoehn Y. et al.: The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia. Leuk. Res. 2008; 32: 1698-708.
61. Lipka D.B., Hoffmann L.S., Heidel F. et al.: LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells. Mol. Cancer Ther. 2008; 7: 1176-84.
62. Reddy M.V., Pallela V.R., Cosenza S.C. et al.: Design, synthesis and evaluation of (E)-alphabenzylthio chalcones as novel inhibitors of BCR-ABL kinase. Bioorg. Med. Chem. 2010; 18: 2317-26.
63. Jatiani S.S., Cosenza S.C., Reddy M.V. et al.: A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition. Genes Cancer 2010; 1: 331-345.
2. James C., Ugo V., Le Couedic J.P. et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-1148.
3. Ma W., Zhang X., Wang X. et al.: MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagn. Mol. Pathol. 2011; 20: 34-9.
4. Panani A.D.: Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disorders: clinical implications. Cancer Lett. 2007; 255: 12-25.
5. Baxter E.J., Scott L.M., Campbell P.J. et al.: Cancer genome project: acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-1061.
6. Passamonti F., Rumi E., Pietra D. et al.: Relation between JAK2 (V617F) mutation status, granulocyte activation and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 2006; 107: 3676-3682.
7. Lippert E., Boissinot M., Kralovics R. et al.: The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006; 108: 1865-1867.
8. Tefferi A., Lasho T.L., Schwager S.M. et al.: The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 2006; 106: 631-635.
9. Jones A.V., Chase A., Silver R.T. et al.: JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat. Genet. 2009; 41: 446-9.
10. Kilpivaara O., Mukherjee S., Schram A.M. et al.: A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat. Genet. 2009; 41: 455-9.
11. Olcaydu D., Harutyunyan A., Jäger R. et al.: A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat. Genet. 2009; 41: 450-4.
12. Pietra D., Li S., Brisci A., Passamonti F. et al.: Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111: 1686-9.
13. Baker S.J., Rane S.G., Reddy E.P.: Hematopoietic cytokine receptor signaling. Oncogene 2007; 26: 6724-37.
14. Jatiani S.S., Baker S.J., Silverman L.R. et al.: JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders: Approaches for Targeted Therapies. Genes Cancer 2010; 1: 979-993.
15. Funakoshi-Tago M., Tago K., Kasahara T. et al.: Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway. Cell Signal. 2008; 20: 1995-2001.
16. Wilks A.F., Harpur A.G., Kurban R.R. 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.
17. Feng J., Witthuhn B.A., Matsuda T. et al.: Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell Biol. 1997; 17: 2497-501.
18. Liu K.D., Gaffen S.L., Goldsmith M.A. et al.: Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Curr. Biol. 1997; 7: 817-26.
19. Saharinen P., Takaluoma K., Silvennoinen O.: Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell Biol. 2000; 20: 3387-95.
20. Lindauer K., Loerting T., Liedl K.R. et al.: 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.
21. 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.
22. 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.
23. Kralovics R., Passamonti F., Buser A.S. et al.: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 2005; 352: 1779-1790.
24. Peeters P., Raynaud S.D., 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.
25. Lacronique V., Boureux A., Valle V.D. et al.: A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278: 1309-12.
26. 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.
27. 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.
28. Murati A., Gelsi-Boyer V., Adélaďde J. et al.: PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia 2005; 19: 1692-6.
29. Adélaďde J., Pérot 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.
30. Bousquet M., Brousset P.: Myeloproliferative disorders carrying the t(8;9) (PCM1-JAK2) translocation. Hum. Pathol. 2006; 37: 500.
31. Griesinger F., Hennig H., Hillmer F. et al.: 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): 9-33.
32. Lane S.W., Fairbairn D.J., McCarthy C. et al.: Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9;22) (p24;q11.2) leading to BCR-JAK2 fusion. Br. J. Haematol. 2008; 142: 503.
33. Poitras J.L., Dal Cin P., Aster J.C. 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.
34. Levine R.L., 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.
35. Tefferi A., Gilliland D.G.: Oncogenes in myeloproliferative disorders. Cell Cycle 2007; 1(6): 550-66.
36. Lee T.S., Ma W., Zhang X. et al.: Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations. Cancer 2009; 115: 1692-700.
37. Dusa A., Mouton C., Pecquet Ch. et al.: JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors. PLoS ONE 2010; 5: 11157.
38. Lee T.S., Ma W., Zhang Xi et al.: Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations. BMC Structural Biology 2009; 9: 58.
39. 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.
40. Scott L.M., Tong W., Levine R.L. et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 2007; 356: 459-68.
41. Pardanani A., Lasho T.L., Finke C. et al.: Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007; 21: 1960-3.
42. Yeh Y.M., Chen Y.L., Cheng H.Y. et al.: High percentage of JAK2 exon 12 mutation in Asian patients with polycythemia vera. Am. J. Clin. Pathol. 2010; 134: 266-70.
43. Jallades L., Hayette S., Tigaud I. et al.: Emergence of therapy-unrelated CML on a background of BCR-ABL-negative JAK2V617F-positive chronic idiopathic myelofibrosis. Leuk. Res. 2008; 32: 1608-10.
44. Krämer A., Reiter A., Kruth J. et al.: JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. Lancet Oncol. 2007; 8: 658-60.
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