Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target
Menée in vitro et in vivo, cette étude suggère l'intérêt de développer une thérapie ciblée sur Axl, un récepteur à activité tyrosine kinase, pour le traitement d'une leucémie myéloïde aiguë présentant une duplication interne en tandem du gène FLT3
Approximately 20 to 25% of patients with acute myeloid leukemia (AML) have a constitutively activated FLT3-internal tandem duplication (FLT3-ITD) and these patients exhibit a poor prognosis. Here we report that Axl, a receptor tyrosine kinase (RTK) overexpressed and constitutively active in human AML, targets the RTK FLT3 in FLT3-ITD+ AML. Abrogation of Axl activation by soluble Axl chimeric protein (Axl-Fc) or small interfering RNA (siRNA) diminishes constitutive FLT3 phosphorylation in FLT3-ITD+ AML. In addition, inhibition of Axl activation by Axl-Fc interferes with the physical interaction between Axl and FLT3. We found that Axl-Fc, a pharmacological Axl inhibitor, or siRNA targeting Axl inhibits cell growth, induces cell cycle arrest and apoptosis, and relieves a block in myeloid differentiation of FLT3-ITD+ AML in vitro. Axl-Fc also suppresses the growth of human FLT3-ITD+ AML in vivo. Collectively, our data suggest that Axl contributes to the pathogenesis of FLT3-ITD+ AML through, at least in part, positive regulation of constitutive FLT3 activation. This also suggests that Axl should be pursued as a potential target for the treatment of FLT3-ITD+ AML.