Bcr/Abl Interferes With The Fanconi Anemia/Brca Pathway : Implications In The Chromosomal Instability Of Chronic Myeloid Leukemia Cells
Valeri, Antonio (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))
Alonso-Ferrero, Maria Eugenia (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Río, Paula (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Pujol i Calvet, M. Roser (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Casado, José A. (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))
Pérez, Laura (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))
Jacome, Ariana (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Agirre, Xabier (Universidad de Navarra. Fundación para la Investigación Médica Aplicada)
Calasanz, M.J (Universidad de Navarra. Fundación para la Investigación Médica Aplicada)
Hanenberg, Helmut (Children's Hospital (Duesseldorf). Department of Pediatric Oncology, Hematology and Immunology)
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Prosper, Felipe (Universidad de Navarra. Fundación para la Investigación Médica Aplicada)
Albella, Beatriz (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))
Bueren, Juan (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))

Fecha:	2010
Resumen:	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.
Nota:	This work was supported by grants from the European Program "Life Sciences, Genomics and Biotechnology for Health" (CONSERT; Ref LSHB-CT-2004- 5242), Centro de Investigacio'n en Red de Enfermedades Raras (CIBERER), Comisión Interministerial de Ciencia y Tecnología (SAF2005-00058, SAF 2009-11936 and SAF 2009-027) and Genoma Espanña (FANCOGENE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Anèmia de Fanconi ; Leucèmia mieloide crònica
Publicado en:	PloS one, Vol. 5, Num. 12 (2010) , p. 15525, ISSN 1932-6203

DOI: 10.1371/journal.pone.0015525
PMID: 21203397

13 p, 768.1 KB

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