The Breakage-Fusion-Bridge Cycle Producing MLL Amplification in a Case of Myelodysplastic Syndrome

Abstract

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.