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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anilides / pharmacology*
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Anilides / therapeutic use
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Axl Receptor Tyrosine Kinase
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Gene Duplication / drug effects*
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / genetics*
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Molecular Targeted Therapy
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Quinolines / pharmacology*
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Quinolines / therapeutic use
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RNA, Small Interfering / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Tandem Repeat Sequences / drug effects
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Tandem Repeat Sequences / genetics
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fms-Like Tyrosine Kinase 3 / genetics*
Substances
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Anilides
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Antineoplastic Agents
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GSK 1363089
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Quinolines
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RNA, Small Interfering
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FLT3 protein, human
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Axl Receptor Tyrosine Kinase
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AXL protein, human