Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders

摘要: Summary Background Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis these is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated role cytoplasmic kinase JAK2 patients with disorder. Methods obtained DNA samples from or coding exons were bidirectionally sequenced peripheral-blood granulocytes, T cells, both. Allele-specific PCR, cytogenetic studies, microsatellite Affymetrix single nucleotide polymorphism array analyses, colony assays undertaken on subgroups patients. Findings A point mutation (Val617Phe) was identified 71 (97%) 73 29 (57%) 51 eight (50%) 16 acquired, present variable proportion alters highly conserved valine negative regulatory JH2 domain, predicted to dysregulate activity. It heterozygous most patients, homozygous subset as result mitotic recombination, arose multipotent progenitor capable giving rise erythroid myeloid cells. all erythropoietin-independent colonies. Interpretation acquired noted more than half Its presence colonies demonstrates link growth factor hypersensitivity, key biological feature Relevance practice Identification Val617Phe lays foundation for new approaches diagnosis, classification, treatment