1. ¹Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland
2. ²Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Correspondence: Dr A Arcaro, Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland. E-mail: Alexandre.Arcaro@kispi.unizh.ch

Received 31 January 2007; Revised 23 May 2007; Accepted 23 May 2007; Published online 21 June 2007.

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 p110 and p110 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.