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|Title:||Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors|
Van der Kuip, H.
|Citation:||Blood, 2012; 119(18):4253-4263|
|Publisher:||Amer Soc Hematology|
|Margaret Nieborowska-Skorska... Timothy P. Hughes... et al.|
|Abstract:||Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRCcIII– generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor–resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)–positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRCcIII. In the present study, inhibition of Rac2 by genetic deletion or a smallmolecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondriatargeted catalase, or addition of ROSscavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.|
|Keywords:||Animals; Humans; Mice; Leukemia, Myeloid, Chronic-Phase; Polycythemia Vera; DNA Damage; Disease Progression; Genomic Instability; Reactive Oxygen Species; Methacrylates; Thiazoles; Electron Transport Complex III; rac GTP-Binding Proteins; Catalase; Superoxide Dismutase; Neoplasm Proteins; Fusion Proteins, bcr-abl; Recombinant Fusion Proteins; DNA, Neoplasm; Electron Transport; Membrane Potential, Mitochondrial; Neoplastic Stem Cells; Leukemia, Myeloid, Acute|
|Rights:||© 2012 by The American Society of Hematology|
|Appears in Collections:||Medicine publications|
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