title: Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors.
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. 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.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Kopinski
authors.forename: Regina
authors.initials: R
authors.lastname: Ray
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.forename: Danielle
authors.initials: D
authors.lastname: Ngaba
authors.forename: Sylwia
authors.initials: S
authors.lastname: Flis
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cramer
authors.forename: Mamatha M
authors.initials: MM
authors.lastname: Reddy
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.forename: Tyrone
authors.initials: T
authors.lastname: Penserga
authors.forename: Eliza
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bolton
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Wiktor-Jedrzejczak
authors.forename: Christine
authors.initials: C
authors.lastname: Richardson
authors.forename: Adrienne
authors.initials: A
authors.lastname: Dorrance
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004579:Electron Transport; D014450:Electron Transport Complex III / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D008689:Methacrylates / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011087:Polycythemia Vera / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D002374:Catalase; D004273:DNA, Neoplasm; D014450:Electron Transport Complex III; D016044:Fusion Proteins, bcr-abl; D008689:Methacrylates; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase; D013844:Thiazoles; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C030517:myxothiazol