Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation.
Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation.
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DOI：
10.1016/j.exphem.2009.09.009
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发表时间：
2009-12
影响因子：
2.6
通讯作者：
Arcasoy, Murat O.
中科院分区：
文献类型：
--
作者：
Laubach, Jacob P.;Fu, Ping;Jiang, Xiaohong;Salter, Kelly H.;Potti, Anil;Arcasoy, Murat O.
Polycythemia vera (PV) is characterized by erythrocytosis associated with the presence of the activating JAK2V617F mutation in a variable proportion of hematopoietic cells. JAK2V617F is detected in other myeloproliferative neoplasms, does not appear to be the PV-initiating event, and its specific role in deregulated erythropoiesis in PV is incompletely understood. We investigated the pathogenesis of PV to characterize abnormal proliferation and apoptosis responses and aberrant oncogenic pathway activation in primary PV erythroid precursors. Peripheral blood CD34+ cells isolated from PV patients and healthy controls were grown in liquid culture to expand a population of primary erythroblasts for experiments designed to analyze cellular proliferation, apoptosis, JAK2V617F mutation status, cytokine-dependent protein phosphorylation and gene expression profiling using Affymetrix microarrays. The survival and proliferation of PV erythroblasts were growth factor-dependent under strict serum-free conditions, requiring both erythropoietin (EPO) and stem cell factor. PV erythroblasts exhibited EPO hypersensitivity and enhanced cellular proliferation associated with increased EPO-mediated ERK1/2 phosphorylation. EPO-induced AKT phosphorylation was observed in PV but not normal erythroblasts, an effect associated with apoptosis resistance in PV erythroblasts. Analysis of gene expression and oncogenic pathway activation signatures revealed increased RAS (P<0.01) and PI3-kinase (P<0.05) pathway activation in PV erythroblasts. Deregulated erythropoiesis in PV involves EPO hypersensitivity and apoptosis resistance of erythroid precursor cells associated with abnormally increased activation of RAS-ERK and PI3-kinase-AKT pathways. These data suggest that investigation of the mechanisms of abnormal RAS and PI3-kinase pathway activation in erythroblasts may contribute to our understanding of the molecular pathogenesis of PV.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
2.6
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