Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease
Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease
复制标题
DOI：
10.1182/blood-2010-05-286757
复制
发表时间：
2011-03-10
期刊：
影响因子：
20.3
通讯作者：
Koschmieder, Steffen
中科院分区：
文献类型：
--
作者：
Elling, Christian;Erben, Philipp;Koschmieder, Steffen
FIP1L1-PDGFRA 融合可见于一小部分推定诊断为嗜酸性粒细胞增多综合征 (HES) 的病例。然而，由于大多数 HES 患者缺乏 FIP1L1-PDGFRA，我们研究了他们是否携带 PDGFRA 基因的激活突变。对 87 名 FIP1L1-PDGFRA 阴性 HES 患者的测序揭示了几种新的 PDGFRA 点突变（R481G、L507P、I562M、H570R、H650Q、N659S、L705P、R748G 和 Y849S）。当克隆到 32D 细胞中时，N659S 和 Y849S 以及高表达子的选择 - 还有 H650Q 和 R748G 突变体诱导生长因子非依赖性增殖、克隆生长以及 PDGFRA 和 Stat5 的组成型磷酸化。伊马替尼拮抗 Stat5 磷酸化。涉及659和849位的突变先前已被证明在胃肠道间质瘤中具有转化潜力。由于H650Q和R748G突变体仅具有微弱的转化活性，我们将携带这些突变体或FIP1L1-PDGFRA的32D细胞注射到小鼠体内，发现它们诱发了类似白血病的疾病。口服伊马替尼治疗显着降低体内白血病生长并延长生存期。总之，我们的数据提供证据表明伊马替尼敏感的 PDGFRA 点突变在 HES 的发病机制中发挥重要作用，我们建议应该进行更多的研究来进一步确定 FIP1L1-PDGFRA 阴性 HES 患者中 PDGFRA 突变的频率和治疗反应。 （血。2011；117(10):2935-2943）
The FIP1L1-PDGFRA fusion is seen in a fraction of cases with a presumptive diagnosis of hypereosinophilic syndrome (HES). However, because most HES patients lack FIP1L1-PDGFRA, we studied whether they harbor activating mutations of the PDGFRA gene. Sequencing of 87 FIP1L1-PDGFRA-negative HES patients revealed several novel PDGFRA point mutations (R481G, L507P, I562M, H570R, H650Q, N659S, L705P, R748G, and Y849S). When cloned into 32D cells, N659S and Y849S and-on selection for high expressors-also H650Q and R748G mutants induced growth factor-independent proliferation, clonogenic growth, and constitutive phosphorylation of PDGFRA and Stat5. Imatinib antagonized Stat5 phosphorylation. Mutations involving positions 659 and 849 had been shown previously to possess transforming potential in gastrointestinal stromal tumors. Because H650Q and R748G mutants possessed only weak transforming activity, we injected 32D cells harboring these mutants or FIP1L1-PDGFRA into mice and found that they induced a leukemia-like disease. Oral imatinib treatment significantly decreased leukemic growth in vivo and prolonged survival. In conclusion, our data provide evidence that imatinib-sensitive PDGFRA point mutations play an important role in the pathogenesis of HES and we propose that more research should be performed to further define the frequency and treatment response of PDGFRA mutations in FIP1L1-PDGFRA-negative HES patients. (Blood. 2011;117(10):2935-2943)