Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation

Cancer Res. 2007 Apr 15;67(8):3759-66. doi: 10.1158/0008-5472.CAN-06-4183.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides
  • Cell Differentiation / physiology
  • Cell Growth Processes / physiology
  • Chronic Disease
  • Enzyme Activation
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Hypereosinophilic Syndrome / enzymology
  • Hypereosinophilic Syndrome / metabolism*
  • Hypereosinophilic Syndrome / pathology
  • Imatinib Mesylate
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / biosynthesis*
  • Oncogene Proteins, Fusion / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor alpha / biosynthesis*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • mRNA Cleavage and Polyadenylation Factors / antagonists & inhibitors
  • mRNA Cleavage and Polyadenylation Factors / biosynthesis*
  • mRNA Cleavage and Polyadenylation Factors / metabolism

Substances

  • Benzamides
  • Oncogene Proteins, Fusion
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Pyrimidines
  • STAT5 Transcription Factor
  • mRNA Cleavage and Polyadenylation Factors
  • Imatinib Mesylate
  • FIP1L1-PDGFRA fusion protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3