Annals of Hematology

, Volume 90, Issue 8, pp 939–946

Differential expression of JAK2 and Src kinase genes in response to hydroxyurea treatment in polycythemia vera and essential thrombocythemia

  • Enriqueta Albizua
  • Miguel Gallardo
  • Santiago Barrio
  • Inmaculada Rapado
  • Ana Jimenez
  • Rosa Ayala
  • Daniel Rueda
  • Beatriz Sanchez-Espiridion
  • Eulalia Puigdecanet
  • Blanca Espinet
  • Lourdes Florensa
  • Carles Besses
  • Joaquin Martinez-Lopez
Original Article

Abstract

This study investigates the differential gene expression profile of JAK2V617F-positive myeloproliferative neoplasm (MPN) patients, with and without response to hydroxyurea (HU) treatment. Twenty-one polycythemia vera, 28 essential thrombocythemia, eight secondary erythrocytosis, and 30 controls were studied. Thirty-four genes were overexpressed in patients who did not respond to HU. Of these, some participate in proliferative pathways: MAPK, AKT, Src kinase (SFK), and JAK2 pathway. JAK2 allele burden was similar between groups of responders and nonresponder. A molecular fingerprint distinguishes JAK2V617F-positive MPN patients without response to HU treatment, with overexpression of JAK2, MAPK14, PIK3CA, and SFK genes.

Keywords

Polycythemia vera Essential thrombocythemia Gene expression profile RT-PCR Response to hydroxyurea JAK2 Src family kinase (SFK) 

Supplementary material

277_2011_1179_MOESM1_ESM.doc (39 kb)
Supplementary Data(DOC 39 kb)
277_2011_1179_MOESM2_ESM.xls (80 kb)
Supplementary Table 1(XLS 80 kb)
277_2011_1179_MOESM3_ESM.xls (50 kb)
Supplementary Table 2(XLS 50 kb)

References

  1. 1.
    James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434(7037):1144–1148PubMedCrossRefGoogle Scholar
  2. 2.
    Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al (2007) 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 8:8Google Scholar
  3. 3.
    Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC et al (2009) Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood 113(20):4829–4833PubMedCrossRefGoogle Scholar
  4. 4.
    Goldman JM, Green AR, Holyoake T, Jamieson C, Mesa R, Mughal T et al (2009) Chronic myeloproliferative diseases with and without the Ph chromosome: some unresolved issues. Leukemia 23:1708–1715PubMedCrossRefGoogle Scholar
  5. 5.
    Levine RL, Belisle C, Wadleigh M, Zahrieh D, Lee S, Chagnon P et al (2006) X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood 107(10):4139–4141, Epub 2006 Jan 24PubMedCrossRefGoogle Scholar
  6. 6.
    Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A et al (2006) Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 108(4):1377–1380PubMedCrossRefGoogle Scholar
  7. 7.
    Lambert JR, Everington T, Linch DC, Gale RE (2009) In essential thrombocythemia, multiple JAK2-V617F clones are present in most mutant-positive patients: a new disease paradigm. Blood 114(14):3018–3023PubMedCrossRefGoogle Scholar
  8. 8.
    Li S, Kralovics R, De Libero G, Theocharides A, Gisslinger H, Skoda RC (2008) Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 111(7):3863–3866PubMedCrossRefGoogle Scholar
  9. 9.
    Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360(22):2289–2301PubMedCrossRefGoogle Scholar
  10. 10.
    Vannucchi AM, Guglielmelli P, Tefferi A (2009) Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin 59(3):171–191PubMedCrossRefGoogle Scholar
  11. 11.
    Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D et al (2005) Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353(1):33–45PubMedCrossRefGoogle Scholar
  12. 12.
    Barosi G, Besses C, Birgegard G, Briere J, Cervantes F, Finazzi G et al (2007) A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia 21(2):277–280PubMedCrossRefGoogle Scholar
  13. 13.
    Akerblom L, Ehrenberg A, Graslund A, Lankinen H, Reichard P, Thelander L (1981) Overproduction of the free radical of ribonucleotide reductase in hydroxyurea-resistant mouse fibroblast 3T6 cells. Proc Natl Acad Sci USA 78(4):2159–2163PubMedCrossRefGoogle Scholar
  14. 14.
    Rapado I, Albizua E, Ayala R, Hernandez JA, Garcia-Alonso L, Grande S et al (2008) Validity test study of JAK2 V617F and allele burden quantification in the diagnosis of myeloproliferative diseases. Ann Hematol 87(9):741–749PubMedCrossRefGoogle Scholar
  15. 15.
    Rapado I, Grande S, Albizua E, Ayala R, Hernandez JA, Gallardo M et al (2009) High resolution melting analysis for JAK2 Exon 14 and Exon 12 mutations: a diagnostic tool for myeloproliferative neoplasms. J Mol Diagn 11(2):155–161PubMedCrossRefGoogle Scholar
  16. 16.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550PubMedCrossRefGoogle Scholar
  17. 17.
    Pellagatti A, Vetrie D, Langford CF, Gama S, Eagleton H, Wainscoat JS et al (2003) Gene expression profiling in polycythemia vera using cDNA microarray technology. Cancer Res 63(14):3940–3944PubMedGoogle Scholar
  18. 18.
    Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A et al (2005) Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 106(10):3374–3376PubMedCrossRefGoogle Scholar
  19. 19.
    Schwemmers S, Will B, Waller CF, Abdulkarim K, Johansson P, Andreasson B et al (2007) JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling. Exp Hematol 35(11):1695PubMedCrossRefGoogle Scholar
  20. 20.
    Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K et al (2008) Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia 22(1):87–95PubMedCrossRefGoogle Scholar
  21. 21.
    Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O (1998) Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood 91(10):3734–3745PubMedGoogle Scholar
  22. 22.
    Zaleskas VM, Krause DS, Lazarides K, Patel N, Hu Y, Li S et al (2006) Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS ONE 1:e18PubMedCrossRefGoogle Scholar
  23. 23.
    Wappl M, Jaeger E, Streubel B, Gisslinger H, Schwarzinger I, Valent P et al (2008) Dasatinib inhibits progenitor cell proliferation from polycythaemia vera. Eur J Clin Investig 38(8):578–584CrossRefGoogle Scholar
  24. 24.
    Girodon F, Schaeffer C, Cleyrat C, Mounier M, Lafont I, Santos FD et al (2008) Frequent reduction or absence of detection of the JAK2-mutated clone in JAK2V617F-positive patients within the first years of hydroxyurea therapy. Haematologica 93(11):1723–1727PubMedCrossRefGoogle Scholar
  25. 25.
    Bock O, Neuse J, Hussein K, Brakensiek K, Buesche G, Buhr T et al (2006) Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol 169(2):471–481PubMedCrossRefGoogle Scholar
  26. 26.
    Stetler-Stevenson WG, Bersch N, Golde DW (1992) Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid-potentiating activity. FEBS Lett 296(2):231–234PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Enriqueta Albizua
    • 1
    • 2
  • Miguel Gallardo
    • 1
  • Santiago Barrio
    • 1
  • Inmaculada Rapado
    • 1
  • Ana Jimenez
    • 1
  • Rosa Ayala
    • 1
  • Daniel Rueda
    • 1
  • Beatriz Sanchez-Espiridion
    • 3
  • Eulalia Puigdecanet
    • 4
  • Blanca Espinet
    • 4
  • Lourdes Florensa
    • 4
  • Carles Besses
    • 5
  • Joaquin Martinez-Lopez
    • 1
  1. 1.Servicio de HematologíaHospital Universitario 12 de OctubreMadridSpain
  2. 2.Servicio de Hematología, Hospital Virgen de la SaludToledoSpain
  3. 3.Spanish National Cancer Research Centre (CNIO)MadridSpain
  4. 4.Laboratoris de Citologia Hematológica/Citogenética Molecular. Servei de Patologia, GRETNHEIMIM-Hospital del MarBarcelonaSpain
  5. 5.Servicio de HematologíaIMIM-Hospital del MarBarcelonaSpain

Personalised recommendations