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

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-PDGFR alpha. When introduced into c-Kit(high)Sca-1(+)Lineage(-) cells, FIP1L1-PDGFR alpha 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-PDGFR alpha but not TEL-PDGFR beta enhanced the development of Gr-1(+)IL-5R alpha(+) eosinophil progenitors from c-Kit(high)Sca-1(+)Lineage(-) cells. FIP1L1-PDGFR alpha also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFR alpha 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-PDGFR alpha-induced eosinophil development, FIP1L1-PDGFR alpha was found to more intensely activate MEK1/2 and p38MAPK than TEL-PDGFR beta. In addition, a MEK1/2 inhibitor and a p38MAPK inhibitor suppressed FIP1L1-PDGFR alpha-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFR alpha augmented the expression of C/EBP alpha, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBP alpha and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFR alpha-induced eosinophil development. Furthermore, FIP1L1-PDGFR alpha and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFR alpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38MAPK cascades.