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Molecular Mechanisms Underlying FIP1L1-PDGFRA–Mediated Myeloproliferation

¹ Molecular Immunology Lab, Department of Immunology, University Medical Center, Utrecht, the Netherlands and ² Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium

Requests for reprints: Paul J. Coffer, Department of Immunology, KC02.085.2 University Medical Center, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Phone: 31-30-250-7674; Fax: 31-30-2504305; E-mail: p.j.coffer{at}umcutrecht.nl.

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. [Cancer Res 2007;67(8):3759–66]

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