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Acute Leukemias

Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway

Abstract

Insulin-like growth factor (IGF) signaling plays an important role in various human cancers. Therefore, the role of insulin-like growth factor I (IGF-I) signaling in growth and survival of acute myeloid leukemia (AML) cells was investigated. Expression of the IGF-I receptor (IGF-IR) and its ligand IGF-I were detected in a panel of human AML blasts and cell lines. IGF-I and insulin promoted the growth of human AML blasts in vitro and activated the phosphoinositide 3-kinase (PI3K)/Akt and the extracellular signal-regulated kinase (Erk) pathways. IGF-I-stimulated growth of AML blasts was blocked by an inhibitor of the PI3K/Akt pathway. Moreover, downregulation of the class Ia PI3K isoforms p110β and p110δ by RNA interference impaired IGF-I-stimulated Akt activation, cell growth and survival in AML cells. Proliferation of a panel of AML cell lines and blasts isolated from patients with AML was inhibited by the IGF-IR kinase inhibitor NVP-AEW541 or by an IGF-IR neutralizing antibody. In addition to its antiproliferative effects, NVP-AEW541 sensitized primary AML blasts and cell lines to etoposide-induced apoptosis. Together, our data describe a novel role for autocrine IGF-I signaling in the growth and survival of primary AML cells. IGF-IR inhibitors in combination with chemotherapeutic agents may represent a novel approach to target human AML.

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Acknowledgements

We thank M Lambelet for isolating AML blasts. We thank Drs F Hofmann and MA Pearson (Novartis Pharma) for providing NVP-AEW541. We thank Dr SP Jackson (Australian Center for Blood Diseases) for providing TGX-221 and Dr JS Hayflick (ICOS Corporation) for providing IC87114. We thank Drs J Jiricny, OE Pardo, J Downward, SP Jackson and A Klippel for providing reagents and cell lines. This work was supported by a grant from the Krebsliga Zürich to AA.

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Correspondence to A Arcaro.

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Doepfner, K., Spertini, O. & Arcaro, A. Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia 21, 1921–1930 (2007). https://doi.org/10.1038/sj.leu.2404813

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