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Bcr/Abl Interferes with the Fanconi Anemia/BRCA Pathway: Implications in the Chromosomal Instability of Chronic Myeloid Leukemia Cells

Valeri, A; Alonso-Ferrero, ME; Rio, P; Pujol, MR; Casado, JA; Perez, L; Jacome, A; ... Bueren, JA; + view all (2010) Bcr/Abl Interferes with the Fanconi Anemia/BRCA Pathway: Implications in the Chromosomal Instability of Chronic Myeloid Leukemia Cells. PLOS ONE , 5 (12) , Article e15525. 10.1371/journal.pone.0015525. Green open access

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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 cross-linking 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.

Type: Article
Title: Bcr/Abl Interferes with the Fanconi Anemia/BRCA Pathway: Implications in the Chromosomal Instability of Chronic Myeloid Leukemia Cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0015525
Publisher version: http://dx.doi.org/10.1371/journal.pone.0015525
Language: English
Additional information: Copyright: © 2010 Valeri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: 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 Investigación en Red de Enfermedades Raras (CIBERER), Comisión Interministerial de Ciencia y Tecnología (SAF2005-00058, SAF 2009-11936 and SAF 2009-027) and Genoma España (FANCOGENE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: H.H. may receive royalties based on a license agreement between Indiana University and Takara Shuzo, Ltd., resulting from the sale of the fibronectin fragment CH296 (Retronectin®). The other authors declare no competing financial interests.
Keywords: CHRONIC MYELOGENOUS LEUKEMIA, STRAND BREAK REPAIR, BCR-ABL ONCOGENE, HEMATOPOIETIC-CELLS, DNA-REPAIR, PHOSPHATIDYLINOSITOL 3-KINASE, CENTROSOME AMPLIFICATION, PHILADELPHIA-CHROMOSOME, CYCLE CHECKPOINT, GENOTOXIC STRESS
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1391286
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