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https://hdl.handle.net/2440/74251
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dc.contributor.author | Nieborowska-Skorska, M. | - |
dc.contributor.author | Kopinski, P. | - |
dc.contributor.author | Ray, R. | - |
dc.contributor.author | Hoser, G. | - |
dc.contributor.author | Ngaba, D. | - |
dc.contributor.author | Flis, S. | - |
dc.contributor.author | Cramer, K. | - |
dc.contributor.author | Reddy, M. | - |
dc.contributor.author | Koptyra, M. | - |
dc.contributor.author | Penserga, T. | - |
dc.contributor.author | Glodkowska-Mrowka, E. | - |
dc.contributor.author | Bolton, E. | - |
dc.contributor.author | Holyoake, T. | - |
dc.contributor.author | Eaves, C. | - |
dc.contributor.author | Cerny-Reiterer, S. | - |
dc.contributor.author | Valent, P. | - |
dc.contributor.author | Hochhaus, A. | - |
dc.contributor.author | Hughes, T. | - |
dc.contributor.author | Van der Kuip, H. | - |
dc.contributor.author | Sattler, M. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | Blood, 2012; 119(18):4253-4263 | - |
dc.identifier.issn | 0006-4971 | - |
dc.identifier.issn | 1528-0020 | - |
dc.identifier.uri | http://hdl.handle.net/2440/74251 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Margaret Nieborowska-Skorska... Timothy P. Hughes... et al. | - |
dc.language.iso | en | - |
dc.publisher | Amer Soc Hematology | - |
dc.rights | © 2012 by The American Society of Hematology | - |
dc.source.uri | http://dx.doi.org/10.1182/blood-2011-10-385658 | - |
dc.subject | Animals | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Leukemia, Myeloid, Chronic-Phase | - |
dc.subject | Polycythemia Vera | - |
dc.subject | DNA Damage | - |
dc.subject | Disease Progression | - |
dc.subject | Genomic Instability | - |
dc.subject | Reactive Oxygen Species | - |
dc.subject | Methacrylates | - |
dc.subject | Thiazoles | - |
dc.subject | Electron Transport Complex III | - |
dc.subject | rac GTP-Binding Proteins | - |
dc.subject | Catalase | - |
dc.subject | Superoxide Dismutase | - |
dc.subject | Neoplasm Proteins | - |
dc.subject | Fusion Proteins, bcr-abl | - |
dc.subject | Recombinant Fusion Proteins | - |
dc.subject | DNA, Neoplasm | - |
dc.subject | Electron Transport | - |
dc.subject | Membrane Potential, Mitochondrial | - |
dc.subject | Neoplastic Stem Cells | - |
dc.subject | Leukemia, Myeloid, Acute | - |
dc.title | Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1182/blood-2011-10-385658 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Hughes, T. [0000-0002-0910-3730] [0000-0002-7990-4509] | - |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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