title: Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation.
abstract: The mitochondrial respiratory chain (MRC) consists of protein complexes I, II, III, IV and V that support oxidative phosphorylation (OXPHOS), which depends on electron transport to generate adenosine triphosphate (ATP). Electron "leakage" from the MRC generates reactive oxygen species (ROS). Chronic myeloid leukemia in chronic phase (CML-CP) stem cells (LSCs) produce high levels of mitochondrial ROS, causing oxidative DNA damage, resulting in genomic instability, generating imatinib-resistant BCR-ABL1 kinase mutants and additional chromosomal aberrations. Using global mRNA microarray analysis combined with Ingenuity Pathway Analysis we found that LSCs display enhanced expression of genes encoding MRC complexes I, II, IV and V. However, expression of genes encoding complex III was deregulated. Treatment with imatinib did not correct the aberrant levels of MRC genes. Therefore we postulate that abnormal expression of MRC genes may facilitate electron "leakage" to promote the production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.
authors.affiliation: Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Flis
authors.forename: David
authors.initials: D
authors.lastname: Irvine
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D042822:Genomic Instability; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001549:Benzamides; D045222:Electron Transport Chain Complex Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl