JAK2 mutation

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The JAK2-V617F point mutation is a genetic mutation that causes some myeloproliferative neoplasms (MPN), a group of diseases that result from the malignant degeneration of blood-forming cells.

Molecular mechanism of action

The point mutation results in an exchange of guanine by thymidine at nucleotide position 2343 in the JAK2 gene. The base exchange leads to a substitution of valine by phenylalanine at amino acid position 617 in exon 12 of the JAK2 polypeptide and thus to a dysregulated or permanently activated kinase activity . This in turn activates the JAK-STAT signal path .

The point mutation occurs with different frequencies within the myeloproliferative diseases. The JAK2 mutation is found in 95% of all patients with polycythemia vera and in 50–60% of all patients with essential thrombocythemia and primary myelofibrosis .

The mutation was first described in 2005 and then led to the development of specific Janus kinase inhibitors such as ruxolitinib and tofacitinib , which are successfully used in myeloproliferative diseases when the point mutation is present.

In patients who do not have a JAK2 mutation, mutations could u. a. in the thrombopoietin receptor gene (MPL) can also be detected with activation of the JAK-STAT signaling pathway and in the calreticulin gene.

Meaning of the mutation

Research to date suggests that MPN sufferers who are JAK2 positive are at greater risk of thromboembolic complications. The JAK2 protein plays an important role in signal transduction in the cell. The mutation activates it, so that the affected cells have a permanently increased rate of cell division. The amount of mutated allele thus makes the disease more aggressive.

literature

  • EJ Baxter, LM Scott, PJ Cambell et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. In: Lancet. 2005, 365, pp. 1054-1061.

Individual evidence

  1. ↑ J. Nangalia, CE Massie, EJ Baxter, Nice FL, G. Gundem, DC Wedge, E. Avezov, J. Li, K. Kollmann, DG Kent, A. Aziz, AL Godfrey, J. Hinton, I. Martincorena , P. Van Loo, AV Jones, P. Guglielmelli, P. Tarpey, HP Harding, JD Fitzpatrick, CT Goudie, CA Ortmann, SJ Loughran, K. Raine, DR Jones, AP Butler, JW Teague, S. O'Meara , S. McLaren, M. Bianchi, Y. Silber, D. Dimitropoulou, D. Bloxham, L. Mudie, M. Maddison, B. Robinson, C. Keohane, C. Maclean, K. Hill, K. Orchard, S. Tauro, M.-Q. Du, M. Greaves, D. Bowen, BJP Huntly, CN Harrison, NCP Cross, D. Ron, AM Vannucchi, E. Papaemmanuil, PJ Campbell, AR Green: Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. In: New England Journal of Medicine . 2013, Volume 369, Issue 25 of December 19, 2013, pp. 2391-2405; doi: 10.1056 / NEJMoa1312542