FIP1L1-PDGFR{alpha} Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells

• Published in: The Journal of biological chemistry Vol. 284; no. 12; pp. 7719 - 7732
• Main Authors: Fukushima, Kentaro, Matsumura, Itaru, Ezoe, Sachiko, Tokunaga, Masahiro, Yasumi, Masato, Satoh, Yusuke, Shibayama, Hirohiko, Tanaka, Hirokazu, Iwama, Atsushi, Kanakura, Yuzuru
• Format: Journal Article
• Language: English
• Published: 20.03.2009
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M807489200

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 super(high)Sca-1 super(+)Lineage super(-) 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 super(+)IL-5R{alpha} super(+) eosinophil progenitors from c-Kit super(high)Sca-1 super(+)Lineage super(-) 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 p38 super(MAPK) than TEL-PDGFR beta . In addition, a MEK1/2 inhibitor and a p38 super(MAPK) 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 p38 super(MAPK) cascades.