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Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/74251

Type: Journal article
Title: Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors
Author: Hughes, Timothy Peter
Citation: Blood, 2012; 119(18):4253-4263
Publisher: American Society of Hematology
Issue Date: 2012
ISSN: 0006-4971
1528-0020
School/Discipline: Medicine
Statement of
Responsibility: 
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.
Rights: © 2012 by The American Society of Hematology
RMID: 0020118974
DOI: 10.1182/blood-2011-10-385658
Appears in Collections:Medicine publications
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