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Myeloproliferative Neoplasms

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Neoplastic Hematopathology

Part of the book series: Contemporary Hematology ((CH))

Abstract/Scope of Chapter

Protein tyrosine kinases (PTKs) have been shown to play a critical role in the pathogenesis of myeloproliferative neoplasms (MPNs). A range of chromosomal rearrangements or mutations in MPNs lead to constitutive activation of PTKs and downstream signal transduction pathways, and thus confer proliferative and survival advantage to the neoplastic clone over normal hematopoietic stem/precursor cells. Molecular abnormalities involving PTKs have been used for the diagnosis, classification, detection of minimal residual disease, as well as targeted therapy in MPNs. We describe Philadelphia chromosome-negative MPNs associated with mutations or rearrangements of tyrosine kinase genes, including PV involving JAK2 (V617F, exon 12 mutation), PMF involving JAK2 (V617F) and MPL (W515L/K), ET involving JAK2 (V617F) and MPL (W515L/K), mastocytosis involving KIT D816V, and myeloid neoplasms with eosinophilia involving PDGFRA, PDGFRB, or FGFR1.

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References

  1. Thiele J, Kvasnicka HM, Orazi A, Tefferi A, Birgegard G. Polycythaemia vera. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classfication of tumours of haematopoietic and lymphoid tissues. Lyon: IARC, 2008:40-3.

    Google Scholar 

  2. Thiele J, Kvasnicka HM, Tefferi A, Barosi G, Orazi A, Vardiman JW. Primary myelofibrosis. In: Swerdlow SH, Campo E, Harris NL, eds. WHO classification of tumours of haematopoetic and lymphoid tissues. Lyon, France, IARC Press. 2008:44-7.

    Google Scholar 

  3. Finazzi G. Essential thrombocythemia. Cancer Treat Res 2008;142:51-68.

    PubMed  Google Scholar 

  4. Johansson P. Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 2006;32(3):171-3.

    Article  PubMed  Google Scholar 

  5. Silver RT. Polycythemia vera and other polycythemia syndromes. Cancer Treat Res 2008;142:1-27.

    PubMed  CAS  Google Scholar 

  6. Steensma DP, Tefferi A. Cytogenetic and molecular genetic aspects of essential thrombocythemia. Acta Haematol 2002;108(2):55-65.

    Article  PubMed  CAS  Google Scholar 

  7. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 2005;131(2):208-13.

    Article  PubMed  CAS  Google Scholar 

  8. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia 2008;22(5):905-14.

    Article  PubMed  CAS  Google Scholar 

  9. Dahabreh IJ, Zoi K, Giannouli S, Zoi C, Loukopoulos D, Voulgarelis M. Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res 2009;33(1):67-73.

    Article  PubMed  CAS  Google Scholar 

  10. Theocharides A, Boissinot M, Girodon F, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007;110(1):375-9.

    Article  PubMed  CAS  Google Scholar 

  11. Kussick SJ, Wood BL. Four-color flow cytometry identifies virtually all cytogenetically abnormal bone marrow samples in the workup of non-CML myeloproliferative disorders. Am J Clin Pathol 2003;120(6):854-65.

    Article  PubMed  Google Scholar 

  12. Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009;23(5):905-11.

    Article  PubMed  CAS  Google Scholar 

  13. Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007;21(9):1960-3.

    Article  PubMed  CAS  Google Scholar 

  14. 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(3):1686-9.

    Article  PubMed  CAS  Google Scholar 

  15. Oppliger Leibundgut E, Horn MP, Brunold C, et al. Hematopoietic and endothelial progenitor cell trafficking in patients with myeloproliferative diseases. Haematologica 2006;91(11):1465-72.

    PubMed  Google Scholar 

  16. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365(9464):1054-61.

    PubMed  CAS  Google Scholar 

  17. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434(7037):1144-8.

    Article  PubMed  CAS  Google Scholar 

  18. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106(6):2162-8.

    Article  PubMed  CAS  Google Scholar 

  19. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779-90.

    Article  PubMed  CAS  Google Scholar 

  20. 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(4):387-97.

    Article  PubMed  CAS  Google Scholar 

  21. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood 2005;106(4):1207-9.

    Article  PubMed  CAS  Google Scholar 

  22. Kawamata N, Ogawa S, Yamamoto G, et al. Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. Exp Hematol 2008;36(11):1471-9.

    Article  PubMed  CAS  Google Scholar 

  23. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356(5):459-68.

    Article  PubMed  CAS  Google Scholar 

  24. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;108(10):3472-6.

    Article  PubMed  CAS  Google Scholar 

  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(7):e270.

    Article  Google Scholar 

  26. 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(10):4922-9.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  Google Scholar 

  28. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006;107(11):4274-81.

    Article  PubMed  CAS  Google Scholar 

  29. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007;110(3):840-6.

    Article  PubMed  CAS  Google Scholar 

  30. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008;112(1):141-9.

    Article  PubMed  CAS  Google Scholar 

  31. Dingli D, Grand FH, Mahaffey V, et al. Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. Br J Haematol 2005;130(2):229-32.

    Article  PubMed  CAS  Google Scholar 

  32. Chou JM, Li CY, Tefferi A. Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia. Leuk Res 2003;27(6):499-504.

    Article  PubMed  CAS  Google Scholar 

  33. Liu K, Kralovics R, Rudzki Z, et al. A de novo splice donor mutation in the thrombopoietin gene causes hereditary thrombocythemia in a Polish family. Haematologica 2008;93(5):706-14.

    Article  PubMed  CAS  Google Scholar 

  34. Skoda R, Prchal JT. Lessons from familial myeloproliferative disorders. Semin Hematol 2005;42(4):266-73.

    Article  PubMed  CAS  Google Scholar 

  35. Li S, Kralovics R, De Libero G, Theocharides A, Gisslinger H, Skoda RC. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 2008;111(7):3863-6.

    Article  PubMed  CAS  Google Scholar 

  36. Westwood NB, Gruszka-Westwood AM, Pearson CE, et al. The incidences of trisomy 8, trisomy 9 and D20S108 deletion in polycythaemia vera: an analysis of blood granulocytes using interphase fluorescence in situ hybridization. Br J Haematol 2000;110(4):839-46.

    Article  PubMed  CAS  Google Scholar 

  37. Tefferi A. Primary myelofibrosis. Cancer Treat Res 2008;142:29-49.

    PubMed  Google Scholar 

  38. Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics in myelofibrosis: Literature review and discussion. Eur J Haematol 2009;82(5):329-38.

    Article  PubMed  Google Scholar 

  39. Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 2009;113(25)):6403-10.

    Article  PubMed  CAS  Google Scholar 

  40. Grand FH, Hidalgo-Curtis CE, Ernst T, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009;113(24):6182-92.

    Article  PubMed  CAS  Google Scholar 

  41. Schnittger S, Bacher U, Kern W, Haferlach T, Haferlach C. JAK2V617F as progression marker in CMPD and as cooperative mutation in AML with trisomy 8 and t(8;21): a comparative study on 1103 CMPD and 269 AML cases. Leukemia 2007;21(8):1843-5.

    Article  PubMed  CAS  Google Scholar 

  42. Horny HP, Akin C, Metcalfe DD, et al. Matocytosis. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classfication of tumours of haematopoietic and lymphoid tissues. Lyon: IARC, 2008:54-63.

    Google Scholar 

  43. Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol 2006;19(3):595-615.

    Article  PubMed  CAS  Google Scholar 

  44. Zhao W, Bueso-Ramos CE, Verstovsek S, Barkoh BA, Khitamy AA, Jones D. Quantitative profiling of codon 816 KIT mutations can aid in the classification of systemic mast cell disease. Leukemia 2007;21(7):1574-6.

    Article  PubMed  CAS  Google Scholar 

  45. Escribano L, Orfao A, Diaz-Agustin B, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 1998;91(8):2731-6.

    PubMed  CAS  Google Scholar 

  46. D’Auriol L, Mattei MG, Andre C, Galibert F. Localization of the human c-kit protooncogene on the q11-q12 region of chromosome 4. Hum Genet 1988;78(4):374-6.

    Article  PubMed  Google Scholar 

  47. Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J 1987;6(11):3341-51.

    PubMed  CAS  Google Scholar 

  48. Lim KH, Pardanani A, Tefferi A. KIT and mastocytosis. Acta Haematol 2008;119(4):194-8.

    Article  PubMed  CAS  Google Scholar 

  49. Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 1993;92(4):1736-44.

    Article  PubMed  CAS  Google Scholar 

  50. Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA 1995;92(23):10560-4.

    Article  PubMed  CAS  Google Scholar 

  51. Yavuz AS, Lipsky PE, Yavuz S, Metcalfe DD, Akin C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood 2002;100(2):661-5.

    Article  PubMed  CAS  Google Scholar 

  52. Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2006;8(4):412-9.

    Article  PubMed  CAS  Google Scholar 

  53. Tan A, Westerman D, McArthur GA, Lynch K, Waring P, Dobrovic A. Sensitive detection of KIT D816V in patients with mastocytosis. Clin Chem 2006;52(12):2250-7.

    Article  PubMed  CAS  Google Scholar 

  54. 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(6):817-20.

    PubMed  CAS  Google Scholar 

  55. Cross NC, Reiter A. Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. Acta Haematol 2008;119(4):199-206.

    Article  PubMed  CAS  Google Scholar 

  56. Bain BJ, Gilliland DG, Horny HP, Vardiman JW. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classfication of tumours of haematopoietic and lymphoid tissues. Lyon: IARC, 2008:68-73.

    Google Scholar 

  57. Bain BJ, Fletcher SH. Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome. Immunol Allergy Clin North Am 2007;27(3):377-88.

    Article  PubMed  Google Scholar 

  58. 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(13):1201-14.

    Article  PubMed  CAS  Google Scholar 

  59. Jones AV, Chose A, Silver RT et al. JAK2 haplotype is a mager risk factor for the development of myeloproliferative neoplasms Nature Genetics 2009;41:446-449.

    Google Scholar 

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Authors and Affiliations

  1. Department of Hematopathology, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA

    C. Cameron Yin & Dan Jones

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  1. C. Cameron Yin
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  2. Dan Jones
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Correspondence to C. Cameron Yin .

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  1. M.D. Anderson Cancer Center, The University of Texas, Holcombe Blvd. 1515 , Houston, 77030, U.S.A.

    Dan Jones

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Yin, C.C., Jones, D. (2010). Myeloproliferative Neoplasms. In: Jones, D. (eds) Neoplastic Hematopathology. Contemporary Hematology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-384-8_9

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  • DOI: https://doi.org/10.1007/978-1-60761-384-8_9

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