Molecular Mechanisms Underlying FIP1L1-PDGFRA–Mediated Myeloproliferation

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 granulocytemacrophage 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]

FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia

“…The FIP1L1 portion is, however, a contributing factor to the higher proliferating activity, induced by FIP1L1-PDGFRA. This result is also consistent with a previous study, which shows that the FIP1L1 portion is necessary to activate STAT5 and the PKB/Akt pathway in human hematopoietic progenitor cells [8].…”

“…A previous report indicated that disruption of the juxtamembrane domain of PDGFRA is critical for constitutive activation of the kinase, whereas the FIP1L1 portion is dispensable [7]. Recently, it has been found that the FIP1L1 portion is also necessary for activating STAT5 and PKB/Akt in human hematopoietic progenitor cells [8].…”

Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

“…Nevertheless, it is still the case that the FIP1L1-PDGFRA fusion gene is under control of the FIP1L1 promoter and translation start, and the FIP1L1 part in the fusion may determine the stability and subcellular localization of the fusion protein. Also, while FIP1L1 seems dispensable for transformation of Ba/F3 cells, Buitenhuis et al 64 documented the differences in in vitro colony formation between FIP1L1-PDGFRA transduced CD34 þ cells and cells transduced by a deletion variant lacking part of FIP1L1.…”

“…8,64 The exact mechanism, however, by which FIP1L1-PDGFRa preferentially affects eosinophils remains unclear. The essential role of FIP1L1-PDGFRA is clear from in vitro studies with the EOL-1 cell line, from mouse models of FIP1L1-PDGFRA induced disease, and from the remarkable responses of FIP1L1-PDFGRA-positive CEL patients to imatinib treatment.…”

FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells

“…As for the downstream signaling molecules, FIP1L1-PDGFR␣ was shown to activate STAT5, phosphatidylinositol 3-kinase, and Ras/ERK pathways like other LTKs, such as BCR-ABL, TEL-ABL, TEL-JAK2, and TEL-PDGFR␤ (18). In addition, Buitenhuis et al (22) recently reported that activation of phosphatidylinositol 3-kinase, ERK1/2, and STAT5 is pivotal for FIP1L1/PDGFR␣-induced myeloproliferation.…”