FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells
FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells
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DOI：
10.1074/jbc.m807489200
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发表时间：
2009-03-20
影响因子：
4.8
通讯作者：
Kanakura, Yuzuru
中科院分区：
文献类型：
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作者：
Fukushima, Kentaro;Matsumura, Itaru;Kanakura, Yuzuru
虽然白血病酪氨酸激酶（LTKs）激活一组常见的下游分子，由LTKs引起的白血病的表型是相当不同的。在这里，我们报告了FIP 1 L1-PDGFR α导致嗜酸性粒细胞增多综合征/慢性嗜酸性粒细胞白血病的分子机制。当导入c-Kit（高）Sca-1（+）谱系（-）细胞时，FIP 1 L1-PDGFR α赋予这些细胞非依赖于精氨酸的生长并增强其自我更新，而在体外再铺板测定和移植测定中，它不能使普通髓系祖细胞永生化。重要的是，FIP 1 L1-PDGFR α而不是TEL-PDGFR β增强了c-Kit（高）Sca-1（+）谱系（-）细胞中Gr-1（+）IL-5 R α（+）嗜酸性粒细胞祖细胞的发育。FIP 1 L1-PDGFR α还促进嗜酸性粒细胞从普通髓系祖细胞发育。此外，当在巨核细胞/红细胞祖细胞和普通淋巴祖细胞中表达时，FIP 1 L1-PDGFR α不仅抑制向红系细胞、巨核细胞和B淋巴细胞的分化，而且从巨核细胞/红细胞祖细胞和普通淋巴祖细胞异常发育嗜酸性粒细胞祖细胞。至于FIP 1 L1-PDGFR α诱导嗜酸性粒细胞发展的机制，发现FIP 1 L1-PDGFR α比TEL-PDGFR β更强烈地激活MEK 1/2和p38 MAPK。此外，MEK 1/2抑制剂和p38 MAPK抑制剂抑制FIP 1 L1-PDGFR α促进的嗜酸性粒细胞发育。此外，逆转录-PCR分析显示，FIP 1 L1-PDGFR α增强了C/EBP α、加塔-1和加塔-2的表达，而它几乎不影响PU. 1的表达。此外，针对C/EBP α和加塔-2和加塔-3 KRR的短发夹RNA可作为所有加塔成员的显性阴性形式，抑制FIP 1 L1-PDGFR α诱导的嗜酸性粒细胞发育。此外，在荧光素酶测定中，FIP 1 L1-PDGFR α及其下游Ras抑制PU.1活性。总之，这些结果表明FIP 1 L1-PDGFR α通过Ras/MEK和p38 MAPK级联修饰谱系特异性转录因子的表达和活性来增强嗜酸性粒细胞的发育。
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.