Rac2-mitochondrial respiratory chain complex III-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Nieborowska-Skorska, M. et al. (2012) Rac2-mitochondrial respiratory chain complex III-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors. Blood, (doi: 10.1182/blood-2011-10-385658)

Abstract

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors (TKIs) eliminate the bulk of CML-CP cells, but failed 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 the disease relapse and/or malignant progression to a fatal blast phase. Here 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 accumulation of chromosomal aberrations and TKI-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD) -positive polycythemia vera cells and acute myeloid leukemia cells, respectively, also produce ROS via MRC-cIII. Inhibition of Rac2 by genetic deletion or small molecule inhibitor, and downregulation 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. Altogether, we postulate that 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa
• Authors: Nieborowska-Skorska, M., Kopinski, P.K., Ray, R., Hoser, G., Ngaba, D., Flis, S., Cramer, K., Reddy, M.R., Koptyra, M., Penserga, T., Glodkowska-Mrowka, E., Bolton, E., Holyoake, T.L., Eaves, C.J., Cerny-Reiterer, S., Valent, P., Hochhaus, A., Hughes, T.P., van der Kuip, H., Sattler, M., Wiktor-Jedrzejczak, W., Richardson, C., Dorrance, A., Stoklosa, T., Williams, D.A., and Skorski, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• ISSN: 0006-4971