Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody
Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody
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DOI：
10.3324/haematol.2009.010785
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发表时间：
2010-03-01
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影响因子：
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通讯作者：
Bouscary, Didier
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作者：
Chapuis, Nicolas;Tamburini, Jerome;Bouscary, Didier
背景在多种癌症中都发现了 PI3K/Akt 通路的改变，PI3K 抑制剂的开发代表了一种有前景的癌症治疗方法。在 50% 的急性髓系白血病患者中检测到了组成型 PI3K 激活，反映了原代母细胞的内在致癌失调。然而，导致这种激活的机制目前尚不清楚。由于我们之前报道了急性髓系白血病细胞中的 IGF-1 自分泌，我们研究了 IGF-1 信号传导是否参与 PI3K 的组成型激活。设计和方法我们分析了 40 个急性髓系白血病骨髓样本中的 IGF-1/IGF-1R 信号通路和 PI3K 活性。使用中和抗 IGF-1R、抗 IGF-1 抗体或 ICE-1 短干扰 RNA 研究了 IGF-1/IGF-1R 信号传导的特异性抑制。通过分析中和性抗IGF-1R对白血病祖细胞克隆形成、母细胞增殖和存活的影响来测试其抗白血病活性。结果在所有测试的样本中，我们发现功能性IGF-1R在白血病细胞中持续表达。在PI3K激活的急性髓系白血病样本中，我们发现IGF-1R被组成型磷酸化，尽管没有检测到IGF-1R激活突变。在 70% 的 PI3K 激活样品中，用中和抗 IGF-1R 特异性抑制 IGF-1R 信号传导可强烈抑制 IGF-1R 和 Akt 的组成型磷酸化。此外，与抗 IGE-1 抗体和 IGF-1 短干扰 RNA 一起孵育均可抑制白血病细胞中的 Akt 磷酸化。最后，中和抗 IGF-1R 治疗降低了白血病祖细胞的集落性和 PI3K 激活的急性髓系白血病细胞的增殖。结论我们目前的数据表明 IGF-1 自分泌在原发性急性髓系白血病细胞的组成型 PI3K/Akt 激活中发挥着关键作用，并为将 IGF-1R 作为潜在的新疗法提供了强有力的理由 对于这种疾病。
BackgroundAlterations in the PI3K/Akt pathway are found in a wide range of cancers and the development of PI3K inhibitors represents a promising approach to cancer therapy. Constitutive PI3K activation, reflecting an intrinsic oncogenic deregulation of primary blast cells, is detected in 50% of patients with acute myeloid leukemia. However, the mechanisms leading to this activation are currently unknown. As we previously reported IGF-1 autocriny in acute myeloid leukemia cells, we investigated whether IGF-1 signaling was involved in the constitutive activation of PI3K.Design and MethodsWe analyzed the IGF-1/IGF-1R signaling pathway and PI3K activity in 40 acute myeloid leukemia bone marrow samples. Specific inhibition of IGF-1/IGF-1R signaling was investigated using neutralizing anti-IGF-1R, anti-IGF-1 antibodies or ICE-1 short interfering RNA. The anti-leukemic activity of the neutralizing anti-IGF-1R was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation and survival.ResultsIn all samples tested, we found that functional IGF-1R was constantly expressed in leukemic cells. In the acute myeloid leukemia samples with PI3K activation, we found that the IGF-1R was constitutively phosphorylated, although no IGF-1R activating mutation was detected. Specific inhibition of IGF-1R signaling with neutralizing anti-IGF-1R strongly inhibited the constitutive phosphorylation of both IGF-1R and Akt in 70% of the PI3K activated samples. Moreover, both incubation with anti-IGE-1 antibody and IGF-1 short interfering RNA inhibited Akt phosphorylation in leukemic cells. Finally, neutralizing anti-IGF-1R treatment decreased the clonogenicity of leukemic progenitors and the proliferation of PI3K activated acute myeloid leukemia cells.ConclusionsOur current data indicate a critical role for IGF-1 autocriny in constitutive PI3K/Akt activation in primary acute myeloid leukemia cells and provide a strong rationale for targeting IGF-1R as a potential new therapy for this disease.