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Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients

Leukemia volume 22, pages 870–873 (2008)Cite this article

The Philadelphia chromosome-negative myeloproliferative diseases (MPD) are a group of late-onset, chronic haematopoietic disorders characterized by the clonal proliferation of stem and progenitor cells resulting in an increased output of mature cells of one or more blood cell lineages. A specific acquired mutation in the key haematopoietic kinase, Janus kinase-2 (JAK2), JAK2V617F, occurs within the regulatory pseudokinase JAK homology-2 (JH2) domain of the JAK2 molecule and is proposed to result in release of autoinhibition of the JAK homology-1 (JH1) kinase domain. This lesion, which occurs in exon 14 of JAK2, is associated with >95% of polycythaemia vera (PV) cases and approximately 50% of patients diagnosed with essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF), (reviewed by Kaushansky 2007).1 The JAK2V617F mutation arises in the stem cell compartment consistent with the clonal proliferation of a multipotent progenitor that maintains long-term clonal haematopoiesis.2 Further, the identification of a mutation in a kinase that is associated with multiple cytokine receptors (CR) is consistent with altered growth factor responses observed in PV. For example, the growth of erythropoietin (Epo)-independent ‘endogenous’ erythroid colonies (eBFUE) from bone marrow (BM) and peripheral blood (PB) samples in vitro is a key feature of PV and ET and can be utilized as a diagnostic tool.

Further somatic mutations have been reported in JAK2V617F-negative MPD patients, including a transmembrane mutation in Mpl (Thrombopoietin receptor) in a small proportion of IMF and ET patients,3 and more recently, a cluster of four different mutations in exon 12 of JAK2 has been described in JAK2V617F-negative PV and idiopathic erythrocytosis patients.4, 5 This group of mutations, affecting amino-acid residues F537–E543, lies in a highly conserved region proximal to the JH2 domain of JAK2 and results in altered growth factor responses in vitro and a myeloproliferative phenotype in a murine bone marrow transplant model.4

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Authors and Affiliations

  1. Haematology and Oncology Program, Child Health Research Institute, North Adelaide, South Australia, Australia

    C M Butcher & R J D'Andrea

  2. Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia

    U Hahn, P G Bardy & R J D'Andrea

  3. Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia

    L B To

  4. Department of Genetic Medicine, University of Adelaide, Adelaide, South Australia, Australia

    J Gecz

  5. Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    E J Wilkins & H S Scott

  6. Discipline of Paediatrics and Discipline of Genetics, University of Adelaide, Adelaide, South Australia, Australia

    R J D'Andrea

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Correspondence to R J D'Andrea.

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Butcher, C., Hahn, U., To, L. et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia 22, 870–873 (2008). https://doi.org/10.1038/sj.leu.2404971

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