TAILIEUCHUNG - Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2)

The etiology of PV is unknown. Although nonrandom chromosome abnormalities such as 20q, trisomy 8, and especially 9p, have been documented in up to 30% of untreated PV patients, unlike CML no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—which replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase— appears to have a central role in the pathogenesis of PV. JAK2 is a member of an evolutionarily well-conserved, nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin. | Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases Part 2 Etiology The etiology of PV is unknown. Although nonrandom chromosome abnormalities such as 20q trisomy 8 and especially 9p have been documented in up to 30 of untreated PV patients unlike CML no consistent cytogenetic abnormality has been associated with the disorder. However a mutation in the autoinhibitory pseudokinase domain of the tyrosine kinase JAK2 which replaces valine with phenylalanine V617F causing constitutive activation of the kinase appears to have a central role in the pathogenesis of PV. JAK2 is a member of an evolutionarily well-conserved nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin receptors. It also functions as an obligate chaperone for these receptors in the Golgi apparatus and is responsible for their cell-surface expression. The conformational change induced in the erythropoietin and thrombopoietin receptors following binding to erythropoietin or thrombopoietin leads to JAK2 autophosphorylation receptor phosphorylation and phosphorylation of proteins involved in cell proliferation differentiation and resistance to apoptosis. Transgenic animals lacking JAK2 die as embryos from severe anemia. Constitutive activation of JAK2 can explain the erythropoietinindependent erythroid colony formation and the hypersensitivity of PV erythroid progenitor cells to erythropoietin and other hematopoietic growth factors their resistance to apoptosis in vitro in the absence of erythropoietin their rapid terminal differentiation and their increase in Bcl-XL expression all of which are characteristic in PV. Importantly the JAK2 gene is located on the short arm of chromosome 9 and loss of heterozygosity on chromosome 9p due to uniparental disomy is the most common cytogenetic abnormality in PV. The segment of 9p involved contains the JAK2 locus loss of heterozygosity in this region leads to homozygosity for the .

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• Other Myeloproliferative Diseases
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• JAK2V671F mutation allele burden
• Real time polymerase chain reaction
• BMC Cancer
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• Increased thrombotic
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• Chống lão hóa
• Splicing site
• Hypoxia signaling pathway
• Polycythemia syndrome
• Candidate gene
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