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Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Nieborowska-Skorska, Margaret, Kopinski, Piotr K., Ray, Regina, Hoser, Grazyna, Ngaba, Danielle, Flis, Sylwia, Cramer, Kimberly, Reddy, Mamatha M., Koptyra, Mateusz, Penserga, Tyrone, Glodkowska-Mrowka, Eliza, Bolton, Elisabeth, Holyoake, Tessa L., Eaves, Connie J., Cerny-Reiterer, Sabine, Valent, Peter, Hochhaus, Andreas, Hughes, Timothy P., van der Kuip, Heiko, Sattler, Martin, Wiktor-Jedrzejczak, Wieslaw, Richardson, Christine, Dorrance, Adrienne, Stoklosa, Tomasz, Williams, David A., Skorski, Tomasz·2012·Blood
DOI 10.1182/blood-2011-10-385658
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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.

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Metadata

Authors
Nieborowska-Skorska, M., Kopinski, P. K., Ray, R., Hoser, G., Ngaba, D., Flis, S., Cramer, K., Reddy, M. M., 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., & Skorski, T.
Affiliations
  • Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA;
  • Department of Clinical Cytology, Medical Center for Postgraduate Education, Warsaw, Poland;
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
  • Department of Immunology, Medical University of Warsaw, Warsaw, Poland;
  • Paul O'Gorman Leukemia Research Centre, University of Glasgow, Glasgow, United Kingdom;
  • Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC;
  • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna and Ludwig-Boltzmann Oncology Cluster, Vienna, Austria;
  • Department of Hematology/Oncology, Jena University Hospital, Jena, Germany;
  • Department of Hematology and Centre for Cancer Biology, University of Adelaide School of Medicine, Adelaide, Australia;
  • Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany;
  • Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland;
  • Department of Biology and Center of Bioinformatics, University of North Carolina at Charlotte, Charlotte, NC; and
  • Division of Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA
Venue
Blood
Publisher
American Society of Hematology
Published
2012-05-03
Volume
119
Issue
18
Pages
4253-4263
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2011-10-385658
Cited by
177
References
10
Language
en

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