Abstract
An interstitial deletion on chromosome 4q12 resulting in the formation of the FIP1L1-PDGFRA fusion protein is involved in the pathogenesis of imatinib-sensitive chronic eosinophilic leukemia. The molecular mechanisms underlying the development of disease are largely undefined. Human CD34(+) hematopoietic progenitor cells were used to investigate the role of FIP1L1-PDGFRA in modulating lineage development. FIP1L1-PDGFRA induced both proliferation and differentiation of eosinophils, neutrophils, and erythrocytes in the absence of cytokines, which could be inhibited by imatinib. Whereas expression of FIP1L1-PDGFRA in hematopoietic stem cells and common myeloid progenitors induced the formation of multiple myeloid lineages, expression in granulocyte-macrophage progenitors induced only the development of eosinophils, neutrophils, and myeloblasts. Deletion of amino acids 30 to 233 in the FIP1L1 gene [FIP1L1(1-29)-PDGFRA] gave rise to an intermediate phenotype, exhibiting a dramatic reduction in the number of erythrocytes. FIP1L1-PDGFRA and FIP1L1(1-29)-PDGFRA both induced the activation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in myeloid progenitors, whereas signal transducers and activators of transcription 5 (STAT5) and protein kinase B/c-akt were only activated by FIP1L1-PDGFRA. Dominant-negative STAT5 partially inhibited FIP1L1-PDGFRA-induced colony formation, whereas combined inhibition of phosphatidylinositol-3-kinase and ERK1/2 significantly reversed FIP1L1-PDGFRA-induced colony formation. Taken together, these results suggest that expression of FIP1L1-PDFGRA in human hematopoietic progenitors induce a myeloproliferative phenotype via activation of multiple signaling molecules including phosphatidylinositol-3-kinase, ERK1/2, and STAT5.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides
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Cell Differentiation / physiology
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Cell Growth Processes / physiology
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Chronic Disease
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Enzyme Activation
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Hematopoietic Stem Cells / metabolism*
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Hematopoietic Stem Cells / pathology
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Humans
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Hypereosinophilic Syndrome / enzymology
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Hypereosinophilic Syndrome / metabolism*
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Hypereosinophilic Syndrome / pathology
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Imatinib Mesylate
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Myeloid Cells / metabolism
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Myeloid Cells / pathology
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / biosynthesis*
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Oncogene Proteins, Fusion / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines / pharmacology
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Pyrimidines / pharmacology
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Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor alpha / biosynthesis*
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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STAT5 Transcription Factor / metabolism
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Signal Transduction
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mRNA Cleavage and Polyadenylation Factors / antagonists & inhibitors
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mRNA Cleavage and Polyadenylation Factors / biosynthesis*
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mRNA Cleavage and Polyadenylation Factors / metabolism
Substances
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Benzamides
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Oncogene Proteins, Fusion
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Pyrimidines
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STAT5 Transcription Factor
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mRNA Cleavage and Polyadenylation Factors
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Imatinib Mesylate
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FIP1L1-PDGFRA fusion protein, human
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Receptor, Platelet-Derived Growth Factor alpha
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3