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

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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
Article numbere15525
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010

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Fanconi Anemia
myeloid leukemia
Chromosomal Instability
Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
DNA
Repair
Genomic Instability
cells
Chromosome Aberrations
retroviral vectors
Oncogene Fusion
chromosome aberrations
Aberrations
DNA Repair-Deficiency Disorders
Crosslinking
DNA repair
Amplification
Hematopoietic System
Centrosome

ASJC Scopus subject areas

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

Cite this

Valeri, A., Alonso-Ferrero, M. E., Río, P., Pujol, M. R., Casado, J. A., Pérez, L., ... 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

Bcr/Abl interferes with the Fanconi anemia/BRCA pathway : implications in the chromosomal instability of chronic myeloid leukemia cells. / Valeri, Antonio; Alonso-Ferrero, Maria Eugenia; Río, Paula; Pujol, María Roser; Casado, José A.; Pérez, Laura; Jacome, Ariana; Agirre, Xabier; Calasanz, Maria José; Hanenberg, Helmut; Surrallés, Jordi; Prosper, Felipe; Albella, Beatriz; Bueren, Juan A.

In: PLoS One, Vol. 5, No. 12, e15525, 2010.

Research output: Contribution to journalArticle

Valeri, A, Alonso-Ferrero, ME, Río, P, Pujol, MR, Casado, JA, Pérez, L, Jacome, A, Agirre, X, Calasanz, MJ, Hanenberg, H, Surrallés, J, Prosper, F, Albella, B & Bueren, JA 2010, 'Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells', PLoS One, vol. 5, no. 12, e15525. https://doi.org/10.1371/journal.pone.0015525
Valeri, Antonio ; Alonso-Ferrero, Maria Eugenia ; Río, Paula ; Pujol, María Roser ; Casado, José A. ; Pérez, Laura ; Jacome, Ariana ; Agirre, Xabier ; Calasanz, Maria José ; Hanenberg, Helmut ; Surrallés, Jordi ; Prosper, Felipe ; Albella, Beatriz ; Bueren, Juan A. / Bcr/Abl interferes with the Fanconi anemia/BRCA pathway : implications in the chromosomal instability of chronic myeloid leukemia cells. In: PLoS One. 2010 ; Vol. 5, No. 12.
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