Autocrine IGF-1/IGF-1R Signaling Is Responsible for PI3K/Akt Constitutive Activation in Acute Myeloid Leukemia.

The PI3K/Akt axis is implicated in cell proliferation and survival and appears promising for target inhibition. The constitutive activation of PI3K (PI3K+) that reflects intrinsic cytokine-independent signaling properties of blast cells is detected in 50% of AML samples at diagnosis. Several cytokines and growth factors are known to stimulate the PI3K/Akt pathway, such as FLT-3, SCF or IGF-1 but the mechanisms leading to the constitutive PI3K activation are unknown. The IGF-1/IGF-1R signaling is thought to have a crucial role in the development and progression of cancers. In AML, IGF-1 promotes cell growth and survival via PI3K signaling. As we previously reported an IGF-1 autocrine production in AML leukemic cells, we investigated whether IGF-1/IGF-1R signaling could be responsible for the constitutive activity of PI3K in AML. We show here in primary AML blast cells that IGF-1R is constantly expressed and constitutively phosphorylated in PI3K+ samples. The constitutive phosphorylation of Akt is fully inhibited in 70% of PI3K+ samples by aIR3, a neutralizing anti-IGF-1R monoclonal antibody but neither ERK nor P70S6K phosphorylation are modified by aIR3. Moreover, siRNA-mediated decrease of the IGF-1 autocrine production markedly reduces Akt phosphorylation in leukemic cells. Finally, no mutation is detected within the complete sequence of IGF-1R cDNA from PI3K+ AML samples. In conclusion, the constitutive activity of PI3K/Akt proceed from the activation of IGF-1R due to an IGF-1 autocriny in 70% of PI3K+ primary AML samples. Our current data strengthen the rational of targeted therapy against IGF-1R in AML.