gsk-1363089 and Cell-Transformation--Neoplastic

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.

Topics: Anilides; Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Cell Transformation, Neoplastic; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; fms-Like Tyrosine Kinase 3; Gene Duplication; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Quinolines; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Tandem Repeat Sequences