Somatic Mutations in Polycythaemia Vera and Other Philadelphia Chromosome Negative Myeloproliferative Neoplasms


The just another kinase (JAK) family kinases function as the cognate tyrosine kinases for Type I/II cytokine receptors that lack intrinsic kinase domains. Perhaps the most important is JAK2, which is also a chaperone for the erythropoietin and thrombopoietin receptors as well as the kinase utilised alone or with other JAK kinases in the majority of cytokine receptors. JAK2 can be considered an oncogene because it is responsible for promoting cell proliferation and preventing apoptosis and its constitutive activation causes acute and chronic leukaemias and lymphomas. The most common JAK2‐activating mutation, V617F, is responsible for the clinical phenotype of polycythaemia vera and that of approximately 50% of cases of essential thrombocytosis and primary myelofibrosis. In recent studies of JAK2 inhibitors in primary myelofibrosis there was amelioration of clinical symptoms and a reduction in splenomegaly, supporting an important role of JAK2 in the myeloproliferative phenotype and identifying a new treatment for these disorders.

Key Concepts:

  • The Janus kinase family has a crucial role in hematopoietic and immune cell function.

  • JAK2 V617F‐activating mutation is the most frequent genetic alteration in polycythaemia vera, essential thrombocytosis and primary meylofibrosis.

  • JAK2 V617F has oncogenic properties and is responsible for uncontrolled cell proliferation, inhibition of apoptosis, genetic instability via induction of proto‐oncogenes, reactive oxygen species and promotion of mitotic recombination.

  • JAK2 exon 12 mutations are frequent in JAK2 V617‐negative polycythaemia vera patients.

  • JAK2 mutation alone cannot entirely explain the disease phenotype in the myeloproliferative disorders and genetic predisposition seems to play an important role in both the acquisition of these mutations and disease pathogenesis.

  • The role of JAK2 V617F mutation as a marker for disease prognosis is unresolved.

  • JAK2 inhibitors improve constitutional symptoms and reduce splenomegaly in primary myelofibrosis patients.

Keywords: myeloproliferative neoplasms; polycythaemia vera; essential thrombocytosis; primary myelofibrosis; somatic mutations; JAK2

Figure 1.

JAK2 protein structure and location of point mutations identified in MPNs. JAK2 domains are shown as boxes (red‐kinase and pseudokinase domains, orange – SH2 domain, green – FERM domain). Most common mutations and their locations are shown. Multiple mutations in exon 12 along with references are listed in the table (Albiero et al., ; Bernardi et al., ; Burjanivova et al., ; Butcher et al., ; Li et al., ; Pietra et al., ; Schnittger et al., ; Williams et al., ).



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Further Reading

Alvarez‐Larran A, Ancochea A, Angona A et al. (2012) Red cell mass measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia. Haematologica 97: 1704–1707.

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Spivak JL (2010) An inconvenient truth. Blood 115: 2727–2728.

Thoennissen NH, Krug UO, Lee DH et al. (2010) Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome‐negative myeloproliferative neoplasms. Blood 115: 2882–2890.

Vannucchi AM and Biamonte F (2011) Epigenetics and mutations in chronic myeloproliferative neoplasms. Haematologica 96: 1398–1402.

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Gondek, Lukasz P, and Spivak, Jerry L(Dec 2012) Somatic Mutations in Polycythaemia Vera and Other Philadelphia Chromosome Negative Myeloproliferative Neoplasms. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024249]