title: Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining.
abstract: Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.forename: Can-Lan
authors.initials: CL
authors.lastname: Sun
authors.forename: Hardik
authors.initials: H
authors.lastname: Modi
authors.forename: WenYong
authors.initials: W
authors.lastname: Chen
authors.forename: Timothy R
authors.initials: TR
authors.lastname: O'Connor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Smita
authors.initials: S
authors.lastname: Bhatia
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics* / Q000528:radiation effects; D019457:Chromosome Breakage / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology; D059766:DNA End-Joining Repair / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D050939:Gene Fusion / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D011839:Radiation, Ionizing; D012008:Recurrence
chemical_list: D018952:Antigens, CD34