FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.
FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.
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DOI：
10.1182/blood-2007-11-126268
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发表时间：
2008-09
期刊：
影响因子：
20.3
通讯作者：
Yoshiyuki Yamada;A. Sánchez-Aguilera;E. Brandt;M. McBride;Nabeel J. H. Al-Moamen;F. Finkelman;David A. Williams;J. Cancelas;M. Rothenberg
中科院分区：
文献类型：
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作者：
Yoshiyuki Yamada;A. Sánchez-Aguilera;E. Brandt;M. McBride;Nabeel J. H. Al-Moamen;F. Finkelman;David A. Williams;J. Cancelas;M. Rothenberg
融合基因FIP 1样1/血小板衍生生长因子受体α（FIP 1 L1/PDGFR α，F/P）的表达和失调的c-kit酪氨酸激酶活性与系统性肥大细胞增多症（SM）和慢性嗜酸性粒细胞白血病（CEL）/高嗜酸性粒细胞综合征（HES）相关。我们分析了造血干细胞和祖细胞（HSC/Ps）中的F/P和IL-5的T细胞过表达（F/P阳性CEL小鼠）诱导的小鼠CEL模型中SM的发展和发病机制。与接受IL-5转基因HSC/Ps移植的对照小鼠相比，这些小鼠在骨髓（BM）、脾脏、皮肤和小肠中具有更多的肥大细胞（MC）浸润。此外，在注射中和性抗c-kit抗体的小鼠中，由F/P表达诱导的肠MC浸润严重减少，但没有消除，表明内源性干细胞因子（SCF）/c-kit相互作用与F/P表达协同诱导SM。表达F/P的BM HSC/Ps在体外细胞因子不存在的情况下表现出增殖和MC分化。SCF刺激更大的迁移F/P-表达的MC比模拟载体转导的MC。F/P表达骨髓源性肥大细胞（BMMC）在去乙酰胆碱条件下比模拟载体对照BMMC存活更长时间。增加的增殖和存活与增加的SCF诱导的Akt活化相关。总之，F/P协同促进MC的发展，激活，并在体内和体外的SCF响应的生存。
Expression of the fusion gene FIP1-like 1/platelet-derived growth factor receptor alpha (FIP1L1/PDGFRalpha, F/P) and dysregulated c-kit tyrosine kinase activity are associated with systemic mastocytosis (SM) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). We analyzed SM development and pathogenesis in a murine CEL model induced by F/P in hematopoietic stem cells and progenitors (HSCs/Ps) and T-cell overexpression of IL-5 (F/P-positive CEL mice). These mice had more mast cell (MC) infiltration in the bone marrow (BM), spleen, skin, and small intestine than control mice that received a transplant of IL-5 transgenic HSCs/Ps. Moreover, intestinal MC infiltration induced by F/P expression was severely diminished, but not abolished, in mice injected with neutralizing anti-c-kit antibody, suggesting that endogenous stem cell factor (SCF)/c-kit interaction synergizes with F/P expression to induce SM. F/P-expressing BM HSCs/Ps showed proliferation and MC differentiation in vitro in the absence of cytokines. SCF stimulated greater migration of F/P-expressing MCs than mock vector-transduced MCs. F/P-expressing bone marrow-derived mast cells (BMMCs) survived longer than mock vector control BMMCs in cytokine-deprived conditions. The increased proliferation and survival correlated with increased SCF-induced Akt activation. In summary, F/P synergistically promotes MC development, activation, and survival in vivo and in vitro in response to SCF.