Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/74251
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
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 1528-0020 |
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. |
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 |
DOI: | 10.1182/blood-2011-10-385658 |
Published version: | http://dx.doi.org/10.1182/blood-2011-10-385658 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.