title: Targeting integrin linked kinase and FMS-like tyrosine kinase-3 is cytotoxic to acute myeloid leukemia stem cells but spares normal progenitors.
abstract: Acute myeloid leukemia (AML) is maintained by rare leukemia-initiating cells (L-ICs). FLT3 and/or PI3K pathways are often dysregulated in AML and may be important for L-IC survival. The presence of PI3K pathway intermediate integrin linked kinase (ILK), and FLT3 was confirmed in five L-IC-enriched AML patient samples. Treatment of AML cells with QLT0267, an inhibitor of ILK and FLT3, decreased survival of long-term suspension culture-initiating cells and NOD/SCID mouse L-IC. In contrast, little toxicity toward normal bone marrow progenitors was observed, demonstrating that candidate leukemic stem cells can be eliminated by inhibition of these targets while normal hematopoietic counterparts are spared.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Muranyi
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hogge
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000037:antagonists & inhibitors*; D000099200:Scaffold Protein ILK
chemical_list: D001391:Azo Compounds; D003561:Cytarabine; D003630:Daunorubicin; D038362:Glycogen Synthase Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D034741:RNA, Small Interfering; D051941:fms-Like Tyrosine Kinase 3; D000099200:Scaffold Protein ILK; C552362:QLT 0267; C497970:FLT3 protein, human