BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

Abstract

1.1 Genomic and chromosomal instability in CML An unstable genome is a common hallmark of nearly all solid tumors and most of leukemias in contrast to normal, healthy cells which are able to maintein genome integrity (Negrini et al., 2010). Genomic instability could result from changes in chromosome structure and number as well as changes on the DNA level. Chromosomal instability (CIN) arises from unproper chromosome segregation as well as division defects and leads to aneuploidy (Foijer, 2010), whereas accumulation of mutations and DNA alterations usually is an effect of the defective repair systems and DNA damage response in cancer cells (Economopoulou et al., 2011). Chronic myeloid leukemia (CML) cells expressing the BCR-ABL tyrosine kinase have been found to accumulate mutations as well as chromosomal abnormalities. One of the first indications that CML correlates with additional chromosome changes has been presented in 1987 (Alimena et al., 1987). Moreover, authors showed that the rate of chromosomal anomalies increased during the blastic transformation. In the next years this has been also confirmed by other authors (Hagemeijer, 1987; Johansson et al., 2002; Su et al., 1999; Suzukawa et al., 1997). Later, random aneuploidy rate between chromosomes 9 and 18 has been reported in CML patients – both, untreated as well as upon imatinib therapy (Amiel et al., 2006). In broader analysis of CML patients it was found that chromosomal instability caused by centrosomal aberrations significantly correlated with the disease progression (Giehl et al., 2005). In the chronic phase only one sample out of 18 showed additional karyotypic alterations, in contrast to blast crisis where 73% patients (11/16) displayed additional karyotype alterations. The observation that CML patients have karyotype aberrations was confirmed in other studies where complex chromosomal rearrangements (CCR) were investigated (Babicka et al., 2006). By using cytogenetics, the FISH, and multicolor FISH (mFISH) methods, a very high level of the genomic instability at the chromosomal level, in cells obtained from chronic myeloid leukemia patients was observed. Altogether, it was shown that the aberrations associated with the progression of BCR-ABLpositive CML chronic phase to the aggressive blast crisis include additional chromosomes (Ph1, +8, +19), isochromosome 17q (associated with the loss of p53), reciprocal