Aneuploidy and chromosomal instability are features of cancers that are usually associated with poor prognosis. Whether aneuploidy is a cause or consequence of cancer and its participation in progression of the disease remains an opened question and is subject of hot scientific debate. Some studies suggest that dysfunction in cell cycle checkpoints leads to genomic instability and contribute to tumor progression. The Bcr-Abl oncoprotein plays a major role in the development of chronic myeloid leukemia (CML). Mechanisms participating in the progression from chronic to blast crisis phase remain largely unknown, however chromosomal instability and aneuploidy are common and are likely to be contributory factors. The mitotic checkpoint is a cell cycle control mechanism leading to the accurate segregation of chromosomes during mitosis. As a compromised spindle checkpoint plays a key role in genetic instability, we investigated the influence of Bcr-Abl on the integrity of the mitotic checkpoint. We showed that Bcr-Abl expression was associated with compromised spindle and tetraploid checkpoints leading to aberrant mitoses, centrosomal abnormalities and spindle defects. Bcr-Abl expressing cells escaped from metaphase arrest upon nocodazole treatment and underwent mitotic slippage associated with p53 and p21 induction and 4NG1 arrest. Cells with a high level of Bcr-Abl expression underwent endoreduplication indicating a compromised tetraploid checkpoint. In addition, we found downregulation of mitotic checkpoint genes (Mad2, Bub1, Bub3 and Aurora B), as well as BRCA1 protein, one of key players involved in the division regulation. We have shown for the first time a direct molecular link between the process of aberrant mitosis followed by aneuploidy and chromosomal instability and the level of Bcr-Abl expression. These data have important implications for chemotherapy, suggesting poor responsiveness to agents targeting spindle checkpoints and further demonstrating the promotion of genomic instability by Bcr-Abl.

This work was supported by FEBS Collaborative Experimental Scholarship for Central & Eastern Europe and a grant 2P04A 05729 from the Ministry of Science and Higher Education in Poland.

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