Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation.
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.
Buitenhuis
Miranda
M
Molecular Immunology Lab, Department of Immunology, University Medical Center, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
Verhagen
Liesbeth P
LP
Cools
Jan
J
Coffer
Paul J
PJ
D001549:Benzamides; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002908:Chronic Disease; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D039221:mRNA Cleavage and Polyadenylation Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism
D001549:Benzamides; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D020796:Receptor, Platelet-Derived Growth Factor alpha; D050799:STAT5 Transcription Factor; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human