Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells

Antonio Valeri, Maria Eugenia Alonso-Ferrero, Paula Río, María Roser Pujol, José A. Casado, Laura Pérez, Ariana Jacome, Xabier Agirre, Maria José Calasanz, Helmut Hanenberg, Jordi Surrallés, Felipe Prosper, Beatriz Albella, Juan A. Bueren

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. Although it is well known that CML cells are genetically unstable, the mechanisms accounting for this genomic instability are still poorly understood. Because the Fanconi anemia (FA) pathway is believed to control several mechanisms of DNA repair, we investigated whether this pathway was disrupted in CML cells. Our data show that CML cells have a defective capacity to generate FANCD2 nuclear foci, either in dividing cells or after DNA damage. Similarly, human cord blood CD34+ cells transduced with BCR/ABL retroviral vectors showed impaired FANCD2 foci formation, whereas FANCD2 monoubiquitination in these cells was unaffected. Soon after the transduction of CD34+ cells with BCR/ABL retroviral vectors a high proportion of cells with supernumerary centrosomes was observed. Similarly, BCR/ABL induced a high proportion of chromosomal abnormalities, while mediated a cell survival advantage after exposure to DNA crosslinking agents. Significantly, both the impaired formation of FANCD2 nuclear foci, and also the predisposition of BCR/ABL cells to develop centrosomal and chromosomal aberrations were reverted by the ectopic expression of BRCA1. Taken together, our data show for the first time a disruption of the FA/BRCA pathway in BCR/ABL cells, suggesting that this defective pathway should play an important role in the genomic instability of CML by the co-occurrence of centrosomal amplification and DNA repair deficiencies.

Original languageEnglish (US)
Article numbere15525
JournalPloS one
Volume5
Issue number12
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Valeri, A., Alonso-Ferrero, M. E., Río, P., Pujol, M. R., Casado, J. A., Pérez, L., Jacome, A., Agirre, X., Calasanz, M. J., Hanenberg, H., Surrallés, J., Prosper, F., Albella, B., & Bueren, J. A. (2010). Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. PloS one, 5(12), [e15525]. https://doi.org/10.1371/journal.pone.0015525