Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells

• Published in: Blood Vol. 121; no. 20; pp. 4175 - 4183
• Main Authors: Bolton-Gillespie, Elisabeth, Schemionek, Mirle, Klein, Hans-Ulrich, Flis, Sylwia, Hoser, Grazyna, Lange, Thoralf, Nieborowska-Skorska, Margaret, Maier, Jacqueline, Kerstiens, Linda, Koptyra, Mateusz, Müller, Martin C., Modi, Hardik, Stoklosa, Tomasz, Seferynska, Ilona, Bhatia, Ravi, Holyoake, Tessa L., Koschmieder, Steffen, Skorski, Tomasz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2013; American Society of Hematology
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Benzamides - therapeutic use; Cells, Cultured; DNA Damage - drug effects; Drug Resistance, Neoplasm - genetics; Genomic Instability - drug effects; Genomic Instability - physiology; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Mice; Mice, Transgenic; Myeloid Neoplasia; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Oxidative Stress - drug effects; Oxidative Stress - genetics; Piperazines - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - therapeutic use; Reactive Oxygen Species - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-11-466938

Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROS-induced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP–like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKI-refractory LSCs to the levels detected in normal cells, and CML-CP–like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients. •Imatinib does not prevent accumulation of genomic instability in CML-CP.•Imatinib-refractory leukemia stem cells may be a source of genomic instability in CML-CP.