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Why do we see JAK2 exon 12 mutations in myeloproliferative neoplasms?

Leukemia volume 27, pages 1930–1932 (2013)Cite this article

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The absence of Janus kinase 2 (JAK2) amino-acid substitution V617F in a minority of patients with myeloproliferative neoplasms (MPNs) prompted a search for additional JAK2 mutations, leading to a discovery of a mutation cluster in the 3′ part of JAK2 exon 12.1 These alterations comprise >40 different small deletions/duplications and substitutions of one or more amino acids between phenylalanines F533 and F547, which are located in a linker between the pseudokinase and the SH2 domains.1, 2 However, the reason for such a conspicuous clustering of MPN-associated mutations has been poorly understood.

Although clonal selection of largely in-frame alterations is highly likely to contribute to the observed clustering, the mutation pattern characterized by a large fraction of deletions/duplications suggests misalignment and possible hypermutability of corresponding DNA segments. A hypothetical mechanism was proposed to involve slippage mispairing of direct AGA repeats;3 however, increased local mutation rates may result from a variety of factors, including the nature of genotoxic agents, genomic context of adjacent regions, secondary structure, localized DNA supercoiling and transcription, which in turn may promote secondary structure formation.4

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Acknowledgements

This work was supported by grants from Leukaemia and Lymphoma Research and the Kay Kendall Leukaemia Fund.

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  1. University of Southampton Faculty of Medicine, Southampton, UK

    I Vorechovsky, A V Jones & N C P Cross

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  1. I Vorechovsky
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Correspondence to I Vorechovsky.

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Vorechovsky, I., Jones, A. & Cross, N. Why do we see JAK2 exon 12 mutations in myeloproliferative neoplasms?. Leukemia 27, 1930–1932 (2013). https://doi.org/10.1038/leu.2013.85

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