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Myeloproliferative Neoplasms

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Book cover Molecular Aspects of Hematologic Malignancies

Part of the book series: Principles and Practice ((PRINCIPLES))

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Abstract

This chapter presents the significance of achievements in molecular biology for the group of disorders called myeloproliferative neoplasms in the latest WHO classification. From a clinical point of view, the finding of specific point mutations or gene fusions has finally proven their neoplastic origin. Second, these findings have given clinicians a very useful tool that can simplify diagnostic procedures and make the final diagnosis more precise and reliable. Another advantage is the development of new drugs to target these mutations. While a separate chapter of this book is devoted to chronic myeloid leukemia, here we present the JAK2 and MPL gene mutations in polycythemia vera, essential thrombocythemia, and primary myelofibrosis; the PDGFRA and PDGFRB fusion genes in chronic eosinophilic leukemia; and the KIT gene mutation in systemic mastocytosis. Some new discoveries in this still expanding field are also highlighted.

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References

  • Apperley J, Bain B (2004) The FIP1L1- PDGFRA syndrome: a case of mistaken identity? Blood 104:2999–3000

    Article  CAS  Google Scholar 

  • Barosi G, Bergamaschi G, Marchetti M, Vannucchi AM, Guglielmelli P, Antonioli E, Massa M, Rosti V, Campanell R, Villani L, Viarengo G, Gattoni E, Gerli G, Specchia G, Tinelli C, Rambaldi A, Barbui T (2007) JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 110:4030–4036

    Google Scholar 

  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassilliou GS, Bench AJ, Boyd EM, Curtim N, Scott MA, Erber WN, The Cancer Genome Project, Green AR (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061

    PubMed  CAS  Google Scholar 

  • Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D, Wilkins BS, Reilly JT, Hasselbach HC, Bowman R, Wheatley K, Buck G, Harrison CN, Green AR (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112:141–149

    Article  PubMed  CAS  Google Scholar 

  • Bodemer C, Hermine O, Palmérini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, Hadj-Rabia S, Nasca L, Georgin-Lavialle S, Cohen-Akenine A, Launay JM, Barete S, Feger F, Arock M, Catteau B, Sans B, Stalder JF, Skowron F, Thomas L, Lorette G, Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P (2010) Pediatric mastocytosis is a clonal disease associated with D816 V and other activating c-KIT mutations. J Invest Dermatol 130:804–815

    Article  PubMed  CAS  Google Scholar 

  • Campbell PJ, Grisshammer M, Dohner K, Dohner H, Kusec R, Hasselbach HC, Larsen TS, Pallisgaard N, Giraudier S, Le Bousse-Kerdiles MC, Desterke C, Guerton B, Dupriez B, Bordessoule D, Fenaux P, Kiledijan JJ, Vialard JF, Briere J, Harrison CN, Green AR, Reilly JT (2006) V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood 107:2098–2100

    Article  PubMed  CAS  Google Scholar 

  • Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy A, Boyd EM, Bench AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber WN, Bareford D, Wilkins BS, Reilly JT, Harrison CN, Green AR (2005) Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 366:1945–1953

    Article  PubMed  CAS  Google Scholar 

  • Chen AT, Prchal JT (2010) JAK 2 kinase inhibitors and myeloproliferative disorders. Curr Opin Hematol 17:110–116

    Article  PubMed  CAS  Google Scholar 

  • Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG (2003) 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 348:1201–1214

    Article  PubMed  CAS  Google Scholar 

  • Curtis CE, Grand FH, Waghorn K, Sahoo TP, George J, Cross NC (2007) A novel ETV6-PDGFRB fusion transcript missed by standard screening in a patient with an imatinib responsive chronic myeloproliferative disease. Leukemia 21:1839–1841

    Article  PubMed  CAS  Google Scholar 

  • Dameshek W (1951) Some speculations on the myeloproliferative syndromes. Blood 6:372–375

    PubMed  CAS  Google Scholar 

  • Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  • Ding A, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A, Tsuboi K, Nitta M, Miyazaki H, Iida S, Ueda R (2004) Familial essential thrombocythemia associated with dominant-positive activating mutation of c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 103:4198–4200

    Article  PubMed  CAS  Google Scholar 

  • Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y (1993) 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 92:1736–1744

    Article  PubMed  CAS  Google Scholar 

  • Giebel LB, Strunk KM, Holmes SA, Spritz RA (1992) Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene 7:2207–2217

    PubMed  CAS  Google Scholar 

  • Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartrum CR, Grosveld G (1984) Philadelphia chromosomal breakpoints are clustered within limited region, bcr, on chromosome 22. Cell 36:93–99

    Article  PubMed  CAS  Google Scholar 

  • Guglielmelli P, Barosi G, Speschia G, Rambaldi A, Lo Coco F, Antonoli E, Pieri L, Pancrazzi A, Delaini F, Longo G, Ammatuna E, Liso V, Bosi A, Barbui T, Vannucchi AM (2009) Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK V617F mutated allele. Blood 114:1477–1483

    Article  PubMed  CAS  Google Scholar 

  • Halaburda K, Prejzner W, Szatkowski D, Limon J, Hellmann A (2006) Allogeneic bone marrow transplantation for hypereosinophilic syndrome: long-term follow-up with eradication of FIP1L1-PDGFRA fusion transcript. Bone Marrow Transpl 38:319–320

    Article  CAS  Google Scholar 

  • Hellmann A, Bieniaszewska M (2009) Myeloprolifarative neoplasms—classification, diagnostic and therapeutic options in the light of molecular findings. Eur Haematol (Touch Breifings) 3:57–60

    Google Scholar 

  • James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148

    Article  PubMed  CAS  Google Scholar 

  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790

    Article  PubMed  CAS  Google Scholar 

  • Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A, Skoda RC (2006) Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 108:1377–1380

    Article  PubMed  CAS  Google Scholar 

  • Lambert F, Heimann P, Herens C, Chariot A, Bours V (2007) A case of FIP1L1-PDGFRA—positive chronic eosinophilic leukemia with a rare FIP1L1 breakpoint. J Mol Diagn 9:414–419

    Article  PubMed  CAS  Google Scholar 

  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005) Activating mutation of the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397

    Article  PubMed  CAS  Google Scholar 

  • Mital A, Piskorz A, Lewandowski K, Wasąg B, Limon J, Hellmann A (2011) A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur J Haematol 86:531–535

    Article  PubMed  CAS  Google Scholar 

  • Nussenzveig RH, Swierczek SI, Jelinek J, Gaikwad A, Liu E, Verstovsek S, Prchal JF, Prchal JT (2007) Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol 35:32–38

    Article  PubMed  CAS  Google Scholar 

  • Pardanani A, Fridley BL, Lashlo TL, Gilliland DF, Tefferi A (2008) Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood 111:2785–2789

    Article  PubMed  CAS  Google Scholar 

  • Pardanani A, Lashlo TL, Finke C, Hanson CA, Tefferi A (2007) Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 21:1960–1963

    Article  PubMed  CAS  Google Scholar 

  • Pietra D, Brisci A, Rumi E, Boggi S, Elena C, Pietrelli A, Bordoni R, Ferrari M, Passamonti F, De Bellis G, Cremonesi L, Cazzola M (2011) Deep sequencing reveals double mutation in cis of MPL exon 10 in myeloproliferative neoplasms. Haematologica 96:607–611

    Article  PubMed  Google Scholar 

  • Pignon J, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant J, Tulliez (1997) A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol 96:374–376

    Article  PubMed  CAS  Google Scholar 

  • Pikman Y, Lee BH, Mercher T (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PloS Med 3:e270

    Article  PubMed  Google Scholar 

  • Schaub FX, Looser R, LI S, HaoShen H, Lehmann T, Tichelli A, Skoda RC (2010) Clonal analysis of TET2 and JAK 2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood 115:2003–2007

    Article  PubMed  CAS  Google Scholar 

  • Scott LM, Scott MA, Campbell PJ, Green AR (2006) Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thromocythemia. Blood 108:2435–2437

    Article  PubMed  CAS  Google Scholar 

  • Siemiątkowska A, Bieniaszewska M, Hellmann A, Limon J (2009) JAK2 and MPL mutations in V617F-negative myeloproliferative neoplasms. Leukemia Res 34:387–389

    Article  Google Scholar 

  • Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J (2006) Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFR alpha and is FIP1L1-independent. Proc Natl Acad Sci U S A 103:8078–8083

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon

    Google Scholar 

  • Tefferi A, Lasho TL, Huang J, Finke C, Hanson CA, Mesa RA, Li CY, Wu W, Hanson CA, Pardanani A (2008a) Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia 22:756–761

    Article  PubMed  CAS  Google Scholar 

  • Tefferi A, Verstovesk S, Pardanani A (2008b) How we diagnose and treat WHO-defined systemic mastocytosis in adults. Haematologica 3:6–9

    Article  Google Scholar 

  • Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, Talmant P, Tichelli A, Hermouet S, Skoda RC (2007) Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 110:375–379

    Article  PubMed  CAS  Google Scholar 

  • Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal J, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 37:435–453

    Article  PubMed  CAS  Google Scholar 

  • Van Etten RA, Koschmieder S, Delhommeau F, Perrotti D, Holyoake T, Pardanani A, Mesa R, Green T, Ibrahim AR, Moghal T, Gale P, Goldman J (2011) The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issue. Haematologica 96:590–601

    Article  PubMed  Google Scholar 

  • Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A (2008) Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 22:1299–1307

    Article  PubMed  CAS  Google Scholar 

  • Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, Marfisi RA, Finazzi G, Guerini V, Fabris F, Randi ML, De Stefano V, Caberlon S, Tafuri A, Ruggeri M, Spcchia G, Liso V, Rossi E, Pogliani E, Gugliotta L, Bosi A, Barbui T (2007) Clinical profile of homozygous JAK2 617 V > F mutation in patients with polycythemia vera and essential thrombocythemia. Blood 110:840–846

    Article  PubMed  CAS  Google Scholar 

  • Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG (2006) Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 107:4274–4281

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Transplantology, Medical University of Gdańsk, Dębinki 7, 80-952, Gdańsk, Poland

    Andrzej Hellmann, Maria Bieniaszewska, Witold Prejzner & Aleksandra Leszczyńska

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  1. Andrzej Hellmann
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  2. Maria Bieniaszewska
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  3. Witold Prejzner
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  4. Aleksandra Leszczyńska
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Correspondence to Andrzej Hellmann .

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Editors and Affiliations

  1. International Institute of Molecular and, Trojdena 4, Warszawa, 02-109, Poland

    Michal Witt

  2. , Institute of Human Genetics, Polish Academy of Sciences, ul. Strzeszynska 32, Poznan, 60479, Poland

    Malgorzata Dawidowska

  3. , Department of Pediatric Hematology, Silesian Academy of Medicine, 3 Maja 13-15, Zabrze, 41800, Poland

    Tomasz Szczepanski

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Hellmann, A., Bieniaszewska, M., Prejzner, W., Leszczyńska, A. (2012). Myeloproliferative Neoplasms. In: Witt, M., Dawidowska, M., Szczepanski, T. (eds) Molecular Aspects of Hematologic Malignancies. Principles and Practice. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-29467-9_8

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