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Identification of a Chemoresistant “Oxidative State-Low” Leukemic Subpopulation in CD34+ Human Acute Myeloid Leukemia

Ioannis Kotsianidis, Dimitra Kokkinou, Elena K Siapati, Paraskevi Miltiades, Eleftheria Lamprianidou, George Vassilopoulos, Nicholas C Zoumpos and Alexandros Spyridonidis

Objective: Both normal and malignant stem cells maintain lower levels of reactive oxygen species (ROS), but the redox state in acute myeloid leukemia (AML) has not been thoroughly characterized and the role of ROS in leukemogenesis is still unclear. Herein, we report the identification of a rare but distinct ROSlow subpopulation in primary CD34+ AML samples. Methods: We analysed the ROS state of a number of AML samples by flow cytometry using the redox-sensitive fluorescence dye 2’7;-dichlorodihydrofluorescein diacetate. We FACS-sorted the ROSlow cells and investigated their immunophenotype, in vivo engraftment potential as well as their ability to withstand chemotherapeutic treatment. Results: Compared to the total CD34+ cells the ROSlow subset contained significantly more CMP-like and less GMP-like progenitors and could establish leukemia in NOD/SCID mice. Additionally, ROSlow cells bore a chemoresistant phenotype as they were more quiescent than total CD34+ AML cells, and showed increased in vitro chemoresistance and markedly higher GM-CSF-induced phosphorylation of STAT5. Conclusions: Thus, the ROSlow subpopulation arises as a novel candidate for cell-specific therapeutic targeting in AML. Further studies will help to ascertain the exact role of the ROSlow subset in the pathobiology and clinical management of AML.