Archives for posts with tag: Telomere

Discovering cancer’s causes with the help of MDS

July 19, 2017 //

The Leukaemia Foundation of Australia’s National MDS Day has just passed (14th July… but I was busy eating croissants so this post is a little late).

This time I thought I would tell you about a discovery that was made with the help of MDS.

How do healthy cells turn cancerous? Their DNA gradually accumulates errors. Most of these errors aren’t important, but occasionally they stop the cell from working properly. They might cause a cell to grow out of control – and this can lead to cancer.

Myelodysplastic syndromes, or MDS, are a range of blood disorders caused by such errors in the genes. Some types of MDS are relatively mild, but about a third go on to become acute myeloid leukaemia (AML). Thanks to research on MDS we understand its causes a lot better than we did ten or fifteen years ago.

My lab recently published a paper describing three cases of poor prognosis MDS and one case of AML with unusual but remarkably similar changes to the DNA. This complicated structure could not have been predicted by the standard methods of analysing cancer DNA or chromosomes. These features showed us the likely steps that led to these diseases.

Each long string of DNA is folded up neatly to make a chromosome. This is a Claymation that shows how Barbara McClintock’s classic breakage-fusion-bridge cycle causes chromosome abnormalities. The video shows one way that chromosomes (packages of DNA) can become disorganised.

The telomeres (that cap and protect the ends of the chromosomes) are shown falling off, making sticky chromosome ends which join together (see NOTE 2). It’s well accepted that these changes greatly increase the chance of cancerous gene changes. This process has reproduced many, many times in the lab. The problem is that it’s not often been demonstrated in actual cancers. But we did that.
Sometimes only part of the telomere erodes away – enough is lost that it no longer protects the chromosomes from sticking together. But there can be enough telomere DNA left to be a molecular signature of the telomere.

The arrow points to green dots in the middle of a chromosome. This is the left-over telomere signature that tells us that this abnormal chromosome was made by the joining together of sticky chromosome ends that had their telomeres eroded away. The other green dots are at the chromosome ends. The left and right photos show the same cell but in the right one the abnormal chromosome is identified by its red and blue label.

In our four cases we found that there was a small but non-functional piece of telomere DNA left behind where the two chromosomes joined. Because the telomeres didn’t function, the two chromosome ends could stick together. These caused breakage-fusion-bridge events that caused a protective tumour suppressor gene to be lost, and may have also caused cancer-causing genes to multiply.
MDS and AML have similar genetic causes, so if we learn about the causes of one of them it can help us understand the other. This is often the case with cancer research in a broader sense – if we understand the basic mechanisms in one cancer it can help us understand the mechanisms at work in other cancers better. Telomere fusion could potentially play a role in any cancer, so our MDS research is relevant to cancer research in general.

NOTES

The paper: The dicentric chromosome dic(20;22) is a recurrent abnormality in myelodysplastic syndromes and is a product of telomere fusion. Ruth MacKinnon, Hendrika Duivenvoorden, Lynda Campbell and Meaghan Wall, 2016. Cytogenetic and Genome Research 150(3-4):262-272
The gene errors discussed here usually occur in the body cells rather than the reproductive cells, so they’re not inherited.
For simplicity the Claymation shows telomere fusion in chromosomes that are dividing. In fact it probably occurs when the DNA is unravelled in the interphase nucleus.
This is cross-posted to Fireside Science on the SciFund Challenge network.

Tags breakage-fusion-bridge cycle, dicentric, FISH, MDS, National MDS Day, Telomere, telomere fusion

Categories cancer, cell biology, chromosomes, genetics, leukaemia, leukemia, MDS, Uncategorized

Telomere talk – the long and the short of it

August 9, 2013 //

Telomeres. Apparently that’s the new buzz word in cosmetics . They come in different sizes – as we age they shorten. It’s been suggested that we could lengthen them to cancel the effects of ageing, or shorten them to cure cancer. But what are they?

They’re an integral part of our chromosomes. The 46 long strings of genes in each human cell are folded up to form chromosomes, which we can see down the microscope. The telomeres are at both ends of each chromosome. They protect the ends of the chromosomes, and stop the chromosomes from sticking to each other. Chromosomes joining together can be a cause of cancer – more about how that works when we look at the promised breakage-fusion-bridge clay model (in stop motion hopefully!).

The green spots are telomeres on the blue chromosomes from a leukaemia cell. Spot the two abnormal "ring" chromosomes - no ends, no telomeres.

The green spots mark the telomeres on the chromosomes from a leukaemia cell. Spot the two abnormal “ring” chromosomes – no ends, no telomeres (answer next time).

As we age our telomeres get shorter. Telomere shortening has also been associated with other factors such as extreme psychological stress and toxins, including chemotherapy. As well as cancer, short telomeres have been associated with diabetes, cardiovascular disease, osteoarthritis and other diseases. But it also seems that measures like reducing stress, improving diet and exercise may stop or even reverse this premature telomere shortening.

Here’s the paradox – short telomeres can help trigger cancer, but once established the cancer switches on a telomere-lengthening mechanism (usually an enzyme called telomerase) to survive.

And so different researchers are trying contrasting approaches to manipulating telomeres for improved health.

On the one hand, some researchers are looking at the possibility of using the telomere-activating enzyme telomerase to reverse the effects of ageing. Some cosmetics are already available that contain a chemical that’s been reported to activate telomerase. This same chemical is being tested for use as a treatment for some diseases associated with ageing and short telomeres.

On the other hand, because cancers need telomerase to be able to divide indefinitely, other researchers are looking into the possibility of destroying telomerase as a cancer treatment.

These potential treatments will need extensive testing to see if they work and make sure they don’t have unwanted side effects.

From the search for eternal youth to understanding and curing cancer, we haven’t heard the end of telomeres.

INTERESTED IN MORE DETAIL?

A single fertilised egg cell becomes a mature human by growing and dividing into two, many times over. Each time a chromosome makes a copy of itself the telomeres lose a little bit off their ends. The older we get the shorter our telomeres become, so there’s a limited number of times a cell can divide.

That is, unless an enzyme called telomerase is turned on. This enzyme lengthens the telomeres. If you think about it, although most cells in our bodies are programmed to divide a limited number of times, some cells have been dividing for millenia – germ cells – eggs and sperm. It’s cells like these that need telomerase.

Most cancer cells are also able to divide indefinitely by switching on telomerase.

Once the telomeres are dangerously short the chromosomes can start sticking together and becoming abnormal. This stage is called crisis. The cells don’t function properly, and are a cancer risk, and they stop dividing or self-destruct. There are “tumour suppressors” that look after this self-destruction, but occasionally a cell will bypass this (for example by having a mutated tumour suppressor gene), survive and divide. If the cells divide, these abnormal chromosomes can become more abnormal and turn on cancer genes or lose tumour suppressor genes.

HOW MY RESEARCH FITS IN

This process has mostly been studied in lab animals or cells grown in the laboratory in artificial conditions. So we can extrapolate and suggest that chromosomes with short telomeres can join together and cause cancer. Unfortunately chemotherapy is associated with shortened telomeres, and is a risk factor for leukaemia. These therapy-related leukaemias are usually marked by very abnormal chromosomes. In my own research I’ve identified some abnormal leukaemia chromosomes that have been made by chromosomes joining together at the telomeres. This was done by identifying which chromosomes are joined together, AND by looking at the molecular content of the chromosomes. End-to-end joining of the chromosomes is actually a lot more common than it’s thought, at least for the abnormal chromosomes I’ve looked at. The similarity between risk factors for very abnormal leukaemia chromosomes and shortened telomeres is interesting.

One thing I’d like to do is find out how common this joining together of the chromosome ends is, in other types of abnormal chromosomes in leukaemia (AML), and eventually look at other cancers. It would help understand how these cancers are caused and possibly identify ways to prevent this. Other information from this type of study could identify more genes with a role in cancer. This opens up new possibilities for developing treatments.

“Abnormal chromosomes made by the end-to-end joining of two chromosomes….” – that sounds like a segue into the breakage-fusion-bridge cycle. More on that later.

The last frontier of the Human Genome Project – repetitive DNA.

July 7, 2013 //

In the year 2000 the draft human genome sequence was announced by Tony Blair and Bill Clinton. It was said to be complete in 2003, in time for the 50^th anniversary of the discovery of the structure of DNA. Well actually it wasn’t quite finished. Actually it’s still not finished. Besides the tweaking that still goes on here and there, there are still big gaps. And what’s in these gaps sometimes has a significant role in cancer.

The biggest gaps are centromeres. Centromeres and telomeres are made of what is known as repetitive DNA, and this is hard to sequence. There’s more detail below.

Cancer chromosomes often have centromere or telomere abnormalities. In fact these abnormalities can cause cancer or make it progress faster.

In cancer research there’s a big push to sequence the genomes of different types of cancer to try and understand the many different DNA changes that can cause cancer. Some researchers try to understand telomeres and centromeres and their role in cancer, but in cancer sequencing projects, and also in diagnostics, centromeres and telomeres are pretty much ignored. Although they’re difficult to sequence, the repetitive DNA does make them easy to study by some other techniques.

One of the goals of personalised medicine is to be able to read a person’s complete genome. For cancer this would include the abnormal cancer genome. But at the moment these gaps mean that we can’t describe the abnormal cancer chromosomes from end to end by sequencing them. The approach I use allows me to work out what’s in each chromosome and discover telomere and centromere abnormalities.

HOW DOES MY RESEARCH FIT IN?

By looking at things that most people don’t worry about I’ve overturned a few assumptions and made some unexpected discoveries, particularly about centromeres in leukaemia.

A normal chromosome has one centromere. I found that chromosomes with two centromeres are more common in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) than was thought. I found that most of these chromosomes with two centromeres were probably made by two chromosomes joining together.

Telomeres are at the ends of chromosomes and stop them from sticking to each other, so when the telomeres are eroded, chromosomes can join together. They can be eroded by exposure to chemical toxins, cancer drugs and radiation. So it’s interesting that the leukaemias that are caused by these exposures have more of these two-centromered chromosomes than other leukaemias.

Fluorescent DNA probes can label up centromeres (blue) and genes (red). In this image there is also a chromosome 20 paint – the green regions are from chromosome 20.

MORE DETAIL ON THE SCIENCE

Telomeres and centromeres are made of highly repetitive DNA and make up some of the gaps in the human genome sequence.

Sequencing a genome is like reading a story. But first we cut the book up into tiny fragments. We read them piece by piece, then try to join the pieces together to make the story, by matching the overlapping parts. Where this approach falls apart is that some sections are repetitive. Some pages are made up of a single word or phrase repeated over and over and over and over and over and over (I won’t repeat that hundreds of thousands of times, but you should get the picture). So if a lot of fragments just say the same thing “over and over and over”, it’s very hard to put them together meaningfully.

The centromere guides the chromosome to the two daughter cells during cell division. A normal chromosome has one centromere. When a chromosome has two centromeres (we call this a dicentric chromosome), the chromosome can be pulled in opposite directions, breaking the chromosome and causing more chromosome disorganisation.Telomeres cap the ends of normal healthy chromosomes. One of their functions is to stop the chromosomes from sticking to each other. So when the telomeres are lost or eroded the chromosomes can join together. That’s one way of creating a chromosome with two centromeres.

Telomere loss is a natural part of ageing. There are also many environmental and lifestyle factors that are thought to affect telomere length. Short telomeres are thought to be a cancer risk because dicentric chromosomes are more likely to arise.

Telomeres and centromeres are very important parts of a normal chromosome. You could say they hold the chromosome together. They have a lot of influence on whether chromosomes are normal and stay normal.