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 …

IK Park, A Mishra, J Chandler… - Blood, The Journal …, 2013 - ashpublications.org
IK Park, A Mishra, J Chandler, SP Whitman, G Marcucci, MA Caligiuri
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
Abstract 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 …
Abstract
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 pharmacologic 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.
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