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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.

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