Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells

Abstract

Although signalling through the type I insulin-like growth factor receptor (IGF-IR) maintains the survival of haematopoietic cells, a specific role of IGF-IR in haematological neoplasms remains largely unknown. Chronic myeloid leukaemia (CML) is the most common subtype of chronic myeloproliferative diseases. Typically, CML evolves as a chronic phase (CP) disease that progresses into accelerated (AP) and blast phase (BP) stages. In this study, we show that IGF-IR is universally expressed in four CML cell lines. IGF-IR was expressed in only 30% and 25% of CP and AP patients, respectively, but its frequency of expression increased to 73% of BP patients. Increased expression levels of IGF-IR with CML progression was supported by quantitative real-time PCR that demonstrated significantly higher levels of IGF-IR mRNA in BP patients. Inhibition of IGF-IR decreased the viability and proliferation of CML cell lines and abrogated their growth in soft agar. Importantly, inhibition of IGF-IR decreased the viability of cells resistant to imatinib mesylate including BaF3 cells transfected with p210 BCR-ABL mutants, CML cell lines and primary neoplastic cells from patients. The negative effects of inhibition of IGF-IR were attributable to apoptosis and cell cycle arrest due to alterations of downstream target proteins. Our findings suggest that IGF-IR could represent a potential molecular target particularly for advanced stage or imatinib-resistant cases. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.