RRC ID 12753
Author Fukushima K, Matsumura I, Ezoe S, Tokunaga M, Yasumi M, Satoh Y, Shibayama H, Tanaka H, Iwama A, Kanakura Y.
Title FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells.
Journal J Biol Chem
Abstract Although leukemogenic tyrosine kinases (LTKs) activate a common set of downstream molecules, the phenotypes of leukemia caused by LTKs are rather distinct. Here we report the molecular mechanism underlying the development of hypereosinophilic syndrome/chronic eosinophilic leukemia by FIP1L1-PDGFRalpha. When introduced into c-Kit(high)Sca-1(+)Lineage(-) cells, FIP1L1-PDGFRalpha conferred cytokine-independent growth on these cells and enhanced their self-renewal, whereas it did not immortalize common myeloid progenitors in in vitro replating assays and transplantation assays. Importantly, FIP1L1-PDGFRalpha but not TEL-PDGFRbeta enhanced the development of Gr-1(+)IL-5Ralpha(+) eosinophil progenitors from c-Kit(high)Sca-1(+)Lineage(-) cells. FIP1L1-PDGFRalpha also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFRalpha not only inhibited differentiation toward erythroid cells, megakaryocytes, and B-lymphocytes but aberrantly developed eosinophil progenitors from megakaryocyte/erythrocyte progenitors and common lymphoid progenitors. As for the mechanism of FIP1L1-PDGFRalpha-induced eosinophil development, FIP1L1-PDGFRalpha was found to more intensely activate MEK1/2 and p38(MAPK) than TEL-PDGFRbeta. In addition, a MEK1/2 inhibitor and a p38(MAPK) inhibitor suppressed FIP1L1-PDGFRalpha-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFRalpha augmented the expression of C/EBPalpha, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBPalpha and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFRalpha-induced eosinophil development. Furthermore, FIP1L1-PDGFRalpha and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFRalpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38(MAPK) cascades.
Volume 284(12)
Pages 7719-32
Published 2009-3-20
DOI 10.1074/jbc.M807489200
PII S0021-9258(20)32484-4
PMID 19147501
PMC PMC2658066
MeSH Animals CCAAT-Enhancer-Binding Protein-alpha / genetics CCAAT-Enhancer-Binding Protein-alpha / metabolism Cell Differentiation* Cells, Cultured Chronic Disease Cytokines / genetics Cytokines / metabolism Eosinophils / enzymology* Eosinophils / pathology GATA1 Transcription Factor / genetics GATA1 Transcription Factor / metabolism GATA2 Transcription Factor / genetics GATA2 Transcription Factor / metabolism Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells Humans Hypereosinophilic Syndrome / enzymology* Hypereosinophilic Syndrome / genetics Hypereosinophilic Syndrome / metabolism Hypereosinophilic Syndrome / pathology MAP Kinase Kinase 1 / genetics MAP Kinase Kinase 1 / metabolism MAP Kinase Kinase 2 / genetics MAP Kinase Kinase 2 / metabolism MAP Kinase Signaling System* Mice Oncogene Proteins, Fusion / genetics Oncogene Proteins, Fusion / metabolism* Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Receptor, Platelet-Derived Growth Factor alpha / genetics Receptor, Platelet-Derived Growth Factor alpha / metabolism* Trans-Activators / genetics Trans-Activators / metabolism Transcription, Genetic / genetics Transplantation, Homologous mRNA Cleavage and Polyadenylation Factors / genetics mRNA Cleavage and Polyadenylation Factors / metabolism* p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism
IF 4.238
Times Cited 25
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393) pCS-RfA-CG (RDB04390)