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Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders

¹ Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,
² National Institute of Diabetes, Digestive and Kidney Disease, Laboratory of Genetics and Physiology, National Institutes of Health, Bethesda, MD 20892 USA;
³ Institute of Medical Technology, University of Tampere and Department of Clinical Microbiology, Tampere University Hospital, FIN-33014 Tampere, Finland

SUMMARY

Among tyrosine kinases, the Janus kinases (Jaks) are the only ones known to possess two kinase domains: a C-terminal functional kinase domain and a nonfunctional pseudokinase domain located just N-terminal to the functioning domain. The pseudokinase domain, or Jak homology domain 2 (JH2)—Jaks contain seven domains that are well-conserved by the four Jak family members—lacks a few key residues critical for catalytic activity. The function of the JH2 has remained a mystery, but recent results indicate that the JH2 domain of Jak2 may inhibit kinase activity. New intriguing observations reveal that the majority of individuals afflicted with polycythemia vera, essential thrombocythemia, or chronic idiopathic myelofibrosis (all members of the chronic myeloproliferative disorders family) share the V617F mutation of the Jak2 JH2 domain. Although the mutation occurs, to some degree, in the germ line, it more often presents as an acquired mutation. The mutation might cause a structural change sufficient to prevent negative regulators from binding and inhibiting the kinase, or could place the kinase in a constitutively "on" conformation. The identification of V617F now provides a molecular diagnostic indicator of several chronic myeloproliferative diseases.