BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells

Cell Stem Cell. 2013 Mar 7;12(3):329-41. doi: 10.1016/j.stem.2012.12.013. Epub 2013 Jan 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / drug effects*
  • Oxidative Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Pyrroles / pharmacology
  • Reactive Oxygen Species / metabolism
  • Tumor Cells, Cultured

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Reactive Oxygen Species
  • obatoclax