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Type: Journal article
Title: Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors
Author: Nieborowska-Skorska, M.
Kopinski, P.
Ray, R.
Hoser, G.
Ngaba, D.
Flis, S.
Cramer, K.
Reddy, M.
Koptyra, M.
Penserga, T.
Glodkowska-Mrowka, E.
Bolton, E.
Holyoake, T.
Eaves, C.
Cerny-Reiterer, S.
Valent, P.
Hochhaus, A.
Hughes, T.
Van der Kuip, H.
Sattler, M.
et al.
Citation: Blood, 2012; 119(18):4253-4263
Publisher: Amer Soc Hematology
Issue Date: 2012
ISSN: 0006-4971
Statement of
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
Leukemia, Myeloid, Chronic-Phase
Polycythemia Vera
DNA Damage
Disease Progression
Genomic Instability
Reactive Oxygen Species
Electron Transport Complex III
rac GTP-Binding Proteins
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
DOI: 10.1182/blood-2011-10-385658
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