Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines1,2. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly3. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines4,5. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Spivak, J. L. The chronic myeloproliferative disorders: clonality and clinical heterogeneity. Semin. Hematol. 41 (2 suppl. 3), 1–5 (2004)

  2. 2

    Prchal, J. T. Polycythemia vera and other primary polycythemias. Curr. Opin. Hematol. 12, 112–116 (2005)

  3. 3

    Spivak, J. L. Polycythemia vera: myths, mechanisms, and management. Blood 100, 4272–4290 (2002)

  4. 4

    Prchal, J. F. & Axelrad, A. A. Bone-marrow responses in polycythemia vera. N. Engl. J. Med. 290, 1382 (1974)

  5. 5

    Casadevall, N. et al. Erythroid progenitors in polycythemia vera. Demonstration of their hypersensitivity to erythropoietin using serum-free cultures. Blood 59, 447–451 (1982)

  6. 6

    Ugo, V. et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp. Hematol. 32, 179–187 (2004)

  7. 7

    Witthuhn, B. A. et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74, 227–236 (1993)

  8. 8

    Bernabei, P. et al. Interferon-gamma receptor 2 expression as the deciding factor in human T, B, and myeloid cell proliferation or death. J. Leukoc. Biol. 70, 950–960 (2001)

  9. 9

    Kralovics, R., Guan, Y. & Prchal, J. T. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp. Hematol. 30, 229–236 (2002)

  10. 10

    Najfeld, V., Montella, L., Scalise, A. & Fruchtman, S. Exploring polycythaemia vera with fluorescence in situ hybridization: additional cryptic 9p is the most frequent abnormality detected. Br. J. Haematol. 119, 558–566 (2002)

  11. 11

    Kralovics, R., Stockton, D. W. & Prchal, J. T. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 102, 3793–3796 (2003)

  12. 12

    Saharinen, P., Takaluoma, K. & Silvennoinen, O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol. 20, 3387–3395 (2000)

  13. 13

    Saharinen, P., Vihinen, M. & Silvennoinen, O. Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol. Biol. Cell 14, 1448–1459 (2003)

  14. 14

    Lindauer, K., Loerting, T., Liedl, K. R. & Kroemer, R. T. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng. 14, 27–37 (2001)

  15. 15

    Argetsinger, L. S. et al. Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol. Cell. Biol. 24, 4955–4967 (2004)

  16. 16

    Feener, E. P., Rosario, F., Dunn, S. L., Stancheva, Z. & Myers, M. G. J. Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling. Mol. Cell. Biol. 24, 4968–4978 (2004)

  17. 17

    Luo, H. et al. Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol. Cell. Biol. 17, 1562–1571 (1997)

  18. 18

    Kohlhuber, F. et al. A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Mol. Cell. Biol. 17, 695–706 (1997)

  19. 19

    Lacronique, V. et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278, 1309–1312 (1997)

  20. 20

    Huang, L. J., Constantinescu, S. N. & Lodish, H. F. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol. Cell 8, 1327–1338 (2001)

  21. 21

    Zhao, S. et al. JAK2, complemented by a second signal from c-kit or flt-3, triggers extensive self-renewal of primary multipotential hemopoietic cells. EMBO J. 21, 2159–2167 (2002)

  22. 22

    Pearson, T. C. & Messinezy, M. The diagnostic criteria of polycythaemia rubra vera. Leuk. Lymphoma 22 (suppl. 1), 87–93 (1996)

  23. 23

    Cools, J. et al. Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. Cytogenet. Cell Genet. 85, 260–266 (1999)

  24. 24

    Le Coniat, M., Romana, S. P. & Berger, R. Partial chromosome 21 amplification in a child with acute lymphoblastic leukemia. Genes Chromosom. Cancer 14, 204–209 (1995)

  25. 25

    Dumoutier, L., Van Roost, E., Colau, D. & Renauld, J. C. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl Acad. Sci. USA 97, 10144–10149 (2000)

  26. 26

    Chagraoui, H. et al. Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO. Blood 101, 2983–2989 (2003)

  27. 27

    Dorsch, M. et al. Ectopic expression of delta4 impairs hematopoietic developement and leads to lymphoproliferative disease. Blood 100, 2046–2055 (2002)

Download references


The authors are grateful to M.-H. Courtier, E. Leclerc and A. Tonon for technical assistance, P. Marynen and J. Cools for providing the human JAK2 cDNA, and J. Feunteun, F. Wendling and O. Bernard for scientific discussions. We thank I. Teyssandier and C. Marzac for their help in collecting polycythaemia vera samples, and J.-C. Brouet, S. Cheze, J.-J. Kiladjian, F. Lellouche, M. Leporrier, M. Macro, P. Morel, O. Reman, L. Roy, A.-L. Taksin, B. Varet and J.-P. Vilque for their help in collecting samples and clinical data. We are also grateful to the patients for their agreement in participating in this study. This work was supported by grants from La Ligue Nationale contre le Cancer (équipe labellisée 2003), la Fédération belge contre le cancer and the FNRS, Belgium. C.J. was supported by a fellowship from the Fondation pour la Recherche Médicale. J.S. was a recipient of a Marie Curie fellowship and of a Daimler-Benz PhD fellowship. S.N.C. is a Research Associate of the FNRS. W.V. is supported by an interface contract between INSERM and IGR.

Author information

Author notes

  1. Chloé James, Valérie Ugo and Jean-Pierre Le Couédic: These authors contributed equally to this work


  1. INSERM U362, Institut Gustave Roussy, Paris XI University, PR1, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France

    • Chloé James
    • , Valérie Ugo
    • , Jean-Pierre Le Couédic
    • , François Delhommeau
    • , Catherine Lacout
    • , Loïc Garçon
    • , Hana Raslova
    • , Annelise Bennaceur-Griscelli
    • , Jean Luc Villeval
    • , Nicole Casadevall
    •  & William Vainchenker
  2. Laboratoire d'Hématologie, CHU Brest, 29609, Brest Cedex, France

    • Valérie Ugo
  3. Laboratoire d'Hématologie, Hôtel Dieu, AP-HP, 75181, Paris, Cedex 04, France

    • Valérie Ugo
    • , François Delhommeau
    •  & Nicole Casadevall
  4. Ludwig Institute for Cancer Research and Christian de Duve Institute of Cellular Pathology & MEXP Unit, Université Catholique de Louvain, B-1200, Brussels, Belgium

    • Judith Staerk
    •  & Stefan N. Constantinescu
  5. INSERM E0210, Hôpital Necker, 75743, Paris, Cedex 15, France

    • Roland Berger
  6. Laboratoire d'Hématologie, Institut Gustave Roussy, 94805, Villejuif Cedex, France

    • Annelise Bennaceur-Griscelli
  7. Polyclinique d'Hématologie, Hôpital Saint Louis, AP-HP, 75475, Paris, Cedex 10, France

    • William Vainchenker


  1. Search for Chloé James in:

  2. Search for Valérie Ugo in:

  3. Search for Jean-Pierre Le Couédic in:

  4. Search for Judith Staerk in:

  5. Search for François Delhommeau in:

  6. Search for Catherine Lacout in:

  7. Search for Loïc Garçon in:

  8. Search for Hana Raslova in:

  9. Search for Roland Berger in:

  10. Search for Annelise Bennaceur-Griscelli in:

  11. Search for Jean Luc Villeval in:

  12. Search for Stefan N. Constantinescu in:

  13. Search for Nicole Casadevall in:

  14. Search for William Vainchenker in:

Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to William Vainchenker.

Supplementary information

  1. Supplementary Method S1

    5'-3' sequences of PCR and sequencing JAK2 primers. This shows all the primer sequences used for DNA amplification and sequencing. (DOC 49 kb)

  2. Supplementary Method S2

    Details of the technique of dual luciferase assays are given. (DOC 14 kb)

About this article

Publication history




Issue Date


Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.