title: Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bolton-Gillespie
authors.forename: Mirle
authors.initials: M
authors.lastname: Schemionek
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Sylwia
authors.initials: S
authors.lastname: Flis
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.forename: Thoralf
authors.initials: T
authors.lastname: Lange
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Maier
authors.forename: Linda
authors.initials: L
authors.lastname: Kerstiens
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Hardik
authors.initials: H
authors.lastname: Modi
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Ilona
authors.initials: I
authors.lastname: Seferynska
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D042822:Genomic Instability / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate
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