title: 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.
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.
authors: Department of Microbiology, Virology, Immunology, and Medical Genetics, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors: Il-Kyoo
authors: IK
authors: Park
authors: Anjali
authors: A
authors: Mishra
authors: Jason
authors: J
authors: Chandler
authors: Susan P
authors: SP
authors: Whitman
authors: Guido
authors: G
authors: Marcucci
authors: Michael A
authors: MA
authors: Caligiuri
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D020440:Gene Duplication / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020080:Tandem Repeat Sequences / Q000187:drug effects / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D034741:RNA, Small Interfering; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human