1. ¹INSERM, U526, Nice, France
2. ²Faculté de Médecine Pasteur (IFR50), Université Nice Sophia-Antipolis. Nice, France
3. ³INSERM, U599, Marseille, France
4. ⁴Aix Marseille Université, IFR137, Marseille, France
5. ⁵Institut Paoli-Calmette, Marseille, France
6. ⁶EMB-Serono Inc, Rockland, MA, USA
7. ⁷Merck Serono International SA, Geneva, Switzerland

Correspondence: Dr J-F Peyron, Faculté de Médecine Pasteur, INSERM U526 (Activation des Cellules Hématopoiétiques et Infections Virales), avenue de Valombrose, 06107, Nice cedex 2, France. E-mail: peyron@unice.fr

Received 24 July 2006; Revised 15 January 2007; Accepted 19 January 2007; Published online 1 March 2007.

Abstract

Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-B) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-B. Pharmacological inhibition of either FLT3 with AG1296 or NF-B with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML.