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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

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

Il-Kyoo Park, Anjali Mishra, Jason Chandler, Susan P Whitman, Guido Marcucci, Michael A Caligiuri

Blood. 2013 Mar 14;121(11):2064-73.

PMID: 23321254

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42411951	Axl active human			Price

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