BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells
Menée sur des échantillons prélevés sur des patients atteints d'une leucémie myéloïde aiguë, cette étude montre que les cellules souches leucémiques, parce qu'elles sont caractérisées par de faibles niveaux d'espèces réactives de l'oxygène, sont sensibles à un traitement à l'aide d'inhibiteurs de BCL-2
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. º LSC are prospectively isolated from the bulk tumor on the basis of low ROS levels º Metabolic dependencies discriminating LSCs, bulk tumor, and normal HSCs are described º BCL-2 is identified as a regulator of LSC mitochondrial respiration º BCL-2 pharmacologic inhibitors demonstrate LSC-specific targeting Human leukemia stem cells upregulate BCL-2 expression as a result of relying on oxidative phosphorylation to produce energy and can therefore be targeted with BCL-2 inhibitors.
http://linkinghub.elsevier.com/retrieve/pii/S1934590912007552