Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells.
Although discovery of the tyrosine kinase inhibitor (TKI) imatinib mesylate has significantly improved the prognosis of chronic myeloid leukemia (CML) patients, a rare population of CML stem cells is known to be resistant to TKI therapy, causing recurrence of CML. However, recent progress in CML stem cell biology may present a novel therapeutic avenue for CML patients. In this review, we focus on mechanisms used by CML stem cells to maintain TKI-resistance. Comprehensive approaches including mouse genetics, prospective identification of CML stem cells, and syngenic transplantation techniques have identified several key molecules or signaling pathways, including hedgehog (Hh)/Smo, promyelocytic leukemia (PML), 5-lipoxygenase (5-LO), and forkhead box class O (FOXO), that function in CML stem cell maintenance. Inhibiting some of these factors in combination with TKI administration successfully antagonized resistance of CML stem cells to TKI therapy, resulting in efficient eradication of leukemia cells in vivo. Thus, development of methods that sensitize CML stem cells to TKI therapy may lead to novel therapies to treat CML patients.
Naka
Kazuhito
K
Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Hoshii
Takayuki
T
Hirao
Atsushi
A
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010087:Oxides / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000187:drug effects / Q000502:physiology
D001152:Arsenicals; D010087:Oxides; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D003561:Cytarabine; D011505:Protein-Tyrosine Kinases; D000077237:Arsenic Trioxide