| http://purl.uniprot.org/citations/22411871 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/22411871 | http://www.w3.org/2000/01/rdf-schema#comment | "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. MRC-cIII-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 MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging 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."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.org/dc/terms/identifier | "doi:10.1182/blood-2011-10-385658"xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Sattler M."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Richardson C."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Ray R."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Williams D.A."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Bolton E."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Valent P."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Reddy M.M."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Hughes T.P."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Cramer K."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Skorski T."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Hochhaus A."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Nieborowska-Skorska M."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Eaves C.J."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Wiktor-Jedrzejczak W."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Holyoake T.L."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Hoser G."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Dorrance A."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "van der Kuip H."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Stoklosa T."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Koptyra M."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Cerny-Reiterer S."xsd:string |
| http://purl.uniprot.org/citations/22411871 | http://purl.uniprot.org/core/author | "Glodkowska-Mrowka E."xsd:string |