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Open Access Highly Accessed Research article

Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations

Tai-Sung Lee1*, Wanlong Ma2, Xi Zhang2, Hagop Kantarjian3 and Maher Albitar2

Author Affiliations

1 Biomedical Informatics and Computational Biology, and Department of Chemistry, University of Minnesota, 207 Pleasant Street, S.E., Minneapolis, MN 55455, USA

2 Quest Diagnostics Nichols Institute, San Juan Capistrano, California, USA

3 Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

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BMC Structural Biology 2009, 9:58  doi:10.1186/1472-6807-9-58

Published: 10 September 2009

Abstract

Background

The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).

Results

Simulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.

Conclusion

The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.