title: BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells.
abstract: Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed "ROS-low"). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
authors: James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors: Eleni D
authors: ED
authors: Lagadinou
authors: Alexander
authors: A
authors: Sach
authors: Kevin
authors: K
authors: Callahan
authors: Randall M
authors: RM
authors: Rossi
authors: Sarah J
authors: SJ
authors: Neering
authors: Mohammad
authors: M
authors: Minhajuddin
authors: John M
authors: JM
authors: Ashton
authors: Shanshan
authors: S
authors: Pei
authors: Valerie
authors: V
authors: Grose
authors: Kristen M
authors: KM
authors: O'Dwyer
authors: Jane L
authors: JL
authors: Liesveld
authors: Paul S
authors: PS
authors: Brookes
authors: Michael W
authors: MW
authors: Becker
authors: Craig T
authors: CT
authors: Jordan
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D017382:Reactive Oxygen Species; C520962:obatoclax