Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas

Telomere maintenance is regarded as a key mechanism in overcoming cellular senescence in tumor cells and in most cases is achieved by the activation o f telomerase, However there is at least one alternative mechanism of telome re lengthening (ALT) which is characterized by heterogeneous and elongated telomeres in the absence of telomerase activity (TA). We evaluated the prev alence of TA, gene expression of telomerase subunits and ALT in relation to telomere morphology and function in matrix producing bone tumors and in os teosarcoma cell lines and present evidence of a direct association of ALT w ith telomere dysfunction and chromosomal instability. Telomere fluorescence in situ hybridization (T-FISH) in ALT cells revealed elongated and shorten ed telomeres, partly in unusual configurations and loci, dicentric marker c hromosomes and signal-free chromosome ends, Free ends give rise to end-to-e nd associations and may induce breakage-fusion-bridge cycles resulting in a n increased number of complex chromosomal rearrangements, as detected by mu ltiplex-FISH (M-FISH). We propose that ALT cannot be seen as an equivalent to telomerase activity in telomere maintenance, Its association with telome re dysfunction and chromosomal instability may have major implications for tumor progression.