Targeting integrin linked kinase and FMS-like tyrosine kinase-3 is cytotoxic to acute myeloid leukemia stem cells but spares normal progenitors.
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.
Muranyi
Andrew L
AL
Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Dedhar
Shoukat
S
Hogge
Donna E
DE
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
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