Isolation and characterization of metabolically distinct leukemic subsets in acute myeloid leukemia

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Κοκκίνου, Δήμητρα
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Overall survival of patients with acute myeloid leukemia (AML) remains low due to the difficulty of preventing and overcoming disease relapse. Emerging evidence has raised the hypothesis that disease recurrence and relapse could be due to a subset of leukemia-initiating cells which have acquired unique biological properties to evade chemotherapy and sustain leukemia growth. So far, several studies have attempted to distinguish the leukemic stem cells (LSC) and showed that reside in the minor, more primitive CD34+/CD38- or CD34-CD38- fractions. However, immunophenotypic characterization may not be sufficient to define LSC. An active area of current research is the significance of Reactive Oxygen Species (ROS) in stem cell biology, as a prospective isolation strategy. ROS are side products of cell’s respiratory chain and regulate numerous cellular processes both in normal stem cells and tumor cells in a dose-depended manner. Here we show that human AML blasts (n=39) contain a distinct population with low ROS levels (median 0,61% of total blasts, range 0,2%-4,99%), as evaluated by flow cytometry using the redox-sensitive fluorescence dye 2',7'-dichlorofluorescein (DCF). We isolated by FACS sorting this “oxidative state-low” leukemic population and found that compared to a ROShigh population, ROSlow cells: a) were more quiescent, b) had increased in vitro chemoresistance and c) revealed potentiated cytokine-induced response of STAT5. ROSlow cells grow colonies in short term colony forming assays and initiate leukemia in NOD/SCID mice. Metabolically distinct leukemic ROSlow cells might be candidate leukemic initiating cells, in similarity with normal hematopoietic stem cells and other cancer stem cells.
Acute myeloid leukemia (AML), Leukemic Stem Cells (LSCs), Reactive Oxygen Species (ROS)