title: BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold.
abstract: Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34+ progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dierov
authors.forename: P V
authors.initials: PV
authors.lastname: Sanchez
authors.forename: B A
authors.initials: BA
authors.lastname: Burke
authors.forename: H
authors.initials: H
authors.lastname: Padilla-Nash
authors.forename: M E
authors.initials: ME
authors.lastname: Putt
authors.forename: T
authors.initials: T
authors.lastname: Ried
authors.forename: M
authors.initials: M
authors.lastname: Carroll
mesh_terms: D016923:Cell Death / Q000235:genetics; D002470:Cell Survival; D043171:Chromosomal Instability / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D005047:Etoposide / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D005047:Etoposide; D016044:Fusion Proteins, bcr-abl