Département d'Hématologie, Institut Cochin, CNRS, UMR8104, Paris, France.
Haematologica. 2010 Mar;95(3):415-23. doi: 10.3324/haematol.2009.010785. Epub 2009 Dec 8.
Alterations 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.
We 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 IGF-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.
In 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-IGF-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.
Our 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.
PI3K/Akt 通路的改变存在于广泛的癌症中，而开发 PI3K 抑制剂代表了癌症治疗的一种有前途的方法。在 50%的急性髓系白血病患者中检测到组成性 PI3K 激活，这反映了原发性原始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 信号是否参与了 PI3K 的组成性激活。
我们分析了 40 例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 IGF-1 短发夹 RNA 来研究 IGF-1/IGF-1R 信号的特异性抑制作用。通过分析其对白血病祖细胞集落生成、原始细胞增殖和存活的影响，测试了中和抗 IGF-1R 的抗白血病活性。
在所测试的所有样本中，我们发现功能性 IGF-1R 始终在白血病细胞中表达。在具有 PI3K 激活的急性髓系白血病样本中，我们发现 IGF-1R 被组成性磷酸化，尽管没有检测到 IGF-1R 激活突变。用中和抗 IGF-1R 特异性抑制 IGF-1R 信号强烈抑制了 70%的 PI3K 激活样本中 IGF-1R 和 Akt 的组成性磷酸化。此外，抗 IGF-1 抗体和 IGF-1 短发夹 RNA 的孵育均抑制了白血病细胞中 Akt 的磷酸化。最后，中和抗 IGF-1R 治疗降低了白血病祖细胞的集落生成能力和 PI3K 激活的急性髓系白血病细胞的增殖。
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中对组成性 PI3K/Akt 激活起关键作用，并为针对 IGF-1R 作为该疾病潜在新疗法提供了强有力的依据。
