Telomere loss may lead to chromosomal instability via the breakage-fusion-bridge (BFB) cycle which can result in genetic amplification and the formation of ring and dicentric chromosomes. This cycle continues until stable chromosomes are formed. The case of a 72-year-old female with refractory anaemia with excess blasts type 2 illustrates these events. Conventional cytogenetics produced a complex karyotype which included unstable abnormalities of chromosomes 11, 12, and 15. Fluorescence in situ hybridization (FISH) analyses including multicolor-FISH (M-FISH) and multicolor-banding (M-BAND) revealed multiple clonal populations with 5 copies of MLL on either a ring chromosome composed entirely of chromosome 11 material or a derivative chromosome composed of chromosomes 11, 12, and 15. The FISH results also clarified the likely evolution of the karyotypic complexity. The simplest cell line contained a dic(12;15) in addition to copy number aberrations that are typical of MDS or AML. As the disease progressed, a ring 11 was formed. Subsequently, the ring 11 appears to have unwound and inserted itself into the dic(12;15) chromosome followed by an inversion of the derivative chromosome, producing a der(11;15;12). Telomeric loss and BFB cycles appear to have played an important role in the chromosomal rearrangements and clonal evolution demonstrated in the karyotype. 1. Introduction Telomeres are composed of repetitive G-rich sequences and proteins that form a dynamic cap to maintain chromosome stability as well as prevent the chromosome ends from degradation and fusion [1]. Telomere loss may lead to the formation of ring and dicentric chromosomes, causing chromosomal instability and genetic amplification via the breakage-fusion-bridge (BFB) cycle [1, 2]. The BFB cycle can be initiated when a chromosome has lost a telomere and is replicated. The ends of the sister chromatids without a telomere may fuse together. A bridge is then formed which breaks during anaphase as the sister chromatids are pulled to opposite poles (Figure 1) [3]. This breakage often occurs very close to the site of fusion [1, 4–6]. The chromatid with the duplication may continue undergoing BFB cycles until a new telomere is acquired to improve stability [4, 7]. A nonhomologous or microhomology mediated end-joining mechanism has been implicated in the repair of broken chromosome ends that is integral to this process [4, 6, 8, 9]. Figure 1: Telomeric loss leading to genetic amplification through breakage-fusion-bridge cycles. Adapted from Bailey and Murnane [ 1]. MLL amplification is found in
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