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Alternative Lengthening of Telomeres
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CMRI’s Cancer Research Unit discovered the Alternative Lengthening of Telomeres (ALT) mechanism in 1995. Since then our focus has gradually shifted to concentrate the majority of our efforts on understanding this mechanism. Around 10 to 15% of all tumours appear to use ALT. We also have a substantial interest in telomerase, and in genes that cooperate with ALT and telomerase in the immortalisation process. Our aim is to understand this process in sufficient molecular detail to be able to design new forms of cancer therapy that block immortalisation.
ALT in tumours
Measuring ALT activity
Turning ALT off
DNA exchange in ALT
Circular DNA in ALT
A new ALT mechanism?
ALT in tumours
A few years ago we discovered that cancer cells that use ALT have unusual structures (that we call ALT-associated PML bodies, or APBs) within their nuclei. We are studying the function of these structures, but we have also found that they are an excellent marker for the presence of ALT in tumours. By detecting APBs in tumour specimens we have found that ALT is particularly common in bone cancers (osteosarcomas), in soft tissue sarcomas, and in the type of brain tumour that is most common in adults (glioblastoma multiforme). Collaborating researchers in the UK (Dr Janice Royds and colleagues) previously showed that the presence of ALT in these brain tumours is highly predictive of the patients' survival. Because of the potential implications for treatment of this cancer, we are now involved in a much larger follow-up study with researchers in New Zealand and Sydney to confirm and extend the results. We are also collaborating with researchers in Milan (Dr Nadia Zaffaroni and colleagues) who are studying ALT in soft tissue sarcomas.
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Measuring ALT activity
Although we now have very reliable methods for detecting whether ALT activity is present or not in cancer cells, we need to be able to measure the amount of activity so that we can determine whether various treatments increase or decrease the activity levels. Over the past several years, we have been developing a rapid measurement procedure. This will speed up the testing of genes and proteins that may be involved in activating or repressing ALT activity, and facilitate screening of compounds to find inhibitors of ALT that can be developed into new anticancer treatments.
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Turning ALT off
We have found that expression of a normal protein, Sp100, at abnormally high levels can switch ALT activity off. This has provided very useful insights into the ALT mechanism. We found that Sp100 exerts this effect by interfering with the function of the MRE11/RAD50/NBS1 protein complex. We expect that this information will eventually be very helpful for developing strategies to switch off ALT in cancers that use this mechanism.
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DNA exchange in ALT
In collaboration with researchers in Paris (Dr Arturo Londoño-Vallejo) and Rome (Dr Silvia Bacchetti), we found that ALT cells have a strikingly high level of DNA exchange at their telomeres. This was discovered independently by research groups in the US. We are carrying out additional studies to determine the significance of this discovery, which is likely to provide additional insights into ALT.
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Circular DNA in ALT
A number of research groups have found that ALT cells contain relatively short pieces of DNA that have the same sequence as telomeric DNA but are separate from chromosomes. Such DNA is referred to as extrachromosomal telomeric repeat (ECTR) DNA, and is found in various forms including linear and circular. We are investigating the location of this DNA within the nucleus, and whether there is an association between ALT activity and the presence of one or more of these ECTR forms.
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A new ALT mechanism?
Over the past few years we have been investigating a cell line that appears to use ALT, but has some unusual properties. Again, a similar discovery was made by another research group in the US. At present it is unclear to us whether this is a variant of minor importance, or whether it is the first known example in human cells of a new ALT mechanism. If it turns out to be a new ALT mechanism, this could have major implications for telomere-targeted cancer treatments.
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