Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells.
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. Be...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-12-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3011007?pdf=render |
| _version_ | 1811225206920839168 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Antonio Valeri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:02:53Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T09:02:53Z |
| publishDate | 2010-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b4a584191bc246d394dc616a54cccc042022-12-22T03:39:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-12-01512e1552510.1371/journal.pone.0015525Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells.Antonio ValeriMaria Eugenia Alonso-FerreroPaula RíoMaría Roser PujolJosé A CasadoLaura PérezAriana JacomeXabier AgirreMaria José CalasanzHelmut HanenbergJordi SurrallésFelipe ProsperBeatriz AlbellaJuan A BuerenChronic 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.http://europepmc.org/articles/PMC3011007?pdf=render |
| spellingShingle | 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 Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. PLoS ONE |
| title | Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. |
| title_full | Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. |
| title_fullStr | Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. |
| title_full_unstemmed | Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. |
| title_short | Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells. |
| title_sort | bcr abl interferes with the fanconi anemia brca pathway implications in the chromosomal instability of chronic myeloid leukemia cells |
| url | http://europepmc.org/articles/PMC3011007?pdf=render |
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