Archives for posts with tag: MDS

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.

Little by little, errors creep into the genes of healthy cells. Most aren’t important. But sometimes they mean the cell doesn’t work the way it’s supposed to. They might cause a cell to grow out of control and turn into cancer.

Myelodysplastic syndromes, or MDS, are a range of blood disorders caused by such errors in the genes. Some types are relatively mild, but about a third progress 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 which described gene changes that were remarkably similar in three cases of poor prognosis MDS and one of AML. Molecularly, the chromosomes had the same complicated structure, that could not have been predicted by the way they looked down the microscope. These features meant that we could work out the steps causing these genetic errors.

This is a Claymation that shows how Barbara McClintock’s classic breakage-fusion-bridge cycle causes gene abnormalities.

The video shows the telomeres (that cap and protect the ends of the chromosomes) falling off, making sticky chromosome ends which join together (see NOTE 2). This is the step that makes cancer-causing gene changes much more likely. It’s well accepted that this eroding away of the telomeres is a mechanism for creating cancerous gene changes. It’s been reproduced many, many times in the lab. The problem is that it’s not often been proven in actual cancers. But we did that.

Sometimes only part of the telomere erodes away – enough that it no longer protects the chromosomes from sticking together. But there’s enough telomere DNA left to be a molecular signature of the telomere.

dic 20-22

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 tested the abnormal chromosomes to see if there was any of the telomere left where the two chromosomes had joined. Indeed this is what we found – the chromosomes had joined together because the chromosome ends had eroded away, leaving a small amount of non-functional telomere DNA. In these instances the ensuing breakage-fusion-bridge events caused a protective tumour suppressor gene to be lost, and, possibly, cancer-causing genes to multiply.

MDS and AML share many gene errors in common, so if we learn about 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

  1. 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
  2. The gene errors discussed here usually occur in the body cells rather than the reproductive cells, so they’re not inherited.
  3. 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.

Dahl - bedtime stories

Roald Dahl had anything but a boring life. I would say he followed his dreams. He told stories that have been loved by children all over the world, like Charlie and the Chocolate Factory and Matilda. He wrote the screenplay for a James Bond movieChitty Chitty Bang Bang and other movies. During World War II he was a fighter pilot and sent intelligence to the spy agency MI6. He died in 1990 from MDS when he was 74. MDS is short for myelodysplastic syndromes, which are a rare group of related diseases in which the blood doesn’t function properly.

Today, the 14th of July, is the third National MDS Day in Australia. A year ago I wrote about Carl Sagan and MDS. Sagan was a very well-known scientist who took quite an interest in his disease, and we can hear him speak about his illness and his fight with it in the media (there’s a link to an interview at the end of this post).

But there’s not much detail, on the internet at least. about Dahl’s illness. One biography just says he went into hospital with an unknown infection in November 1990 and died 11 days later. (Interestingly for me this was the John Radcliffe Hospital in Oxford, UK, and I was working there at the time.) Twenty percent of MDS patients do have infections that are serious enough to need a hospital stay, in fact that’s what finally killed Sagan too.

Organisers of a charity event for MDS in the UK this year took the trouble to explain what MDS is in their advertising material. MDS has a public image problem – almost no public image that is.

  • “Unfortunately (!) the only ‘celebrities’ that have had MDS are all dead (Carl Sagan, Roald Dahl, Susan Sonntag) – if we had a few living ones then maybe this would be a disease with more public profile and hence money for research.”

Myelodysplastic syndromes (MDS for short) can be mild, severe, or anything in between. About a third of people with MDS will get leukaemia (acute myeloid leukaemia or AML).

I’d like to think Mr Dahl would have made a good scientist. Apparently his mother wanted to pay for him to get a good university education but he passed up the offer because he would rather go exploring. He also had a wildly creative imagination, which is always good for investigating things. Indeed, whe did help invent a medical device – the Wade-Dahl-Till valve – that was used to save children with brain injury.

Roald Dahl knew about the importance of vaccination first-hand. His daughter Olivia died from Measles when she was seven. He wrote  a passionate letter pleading with parents to get their children vaccinated.

His widow Felicity set up the Roald Dahl Foundation, which is now known as the Marvellous Children’s Charity. It continues the work he started, helping seriously sick children. I think the Marvellous Mr Dahl would have approved.

SOME LINKS

More about MDS

Carl Sagan talking about his illness:

The Leukaemia Foundation of Australia has information for patients and carers, and supports research in Australia.

There’s also the MDS Beacon, the MDS Foundation, and information available through several other leukaemia and health-related organisations on the net.

More about Roald Dahl

Official website: http://roalddahl.com/

https://en.wikipedia.org/wiki/Roald_Dahl

Biographies

http://www.biographyonline.net/writers/roald-dahl.html

http://www.biography.com/people/roald-dahl-9264648

 

Carl Sagan was an astronomer and academic, best known for popularising astronomy. He hosted and co-produced the original hugely popular series Cosmos: A Personal Voyage.  Its sequel Cosmos: A Spacetime Odyssey was released this year. Even though I’m a biologist at heart I was fascinated by the original Cosmos.

Sagan was diagnosed with a myelodysplastic syndrome (MDS) and died at the age of 62, in 1996. In interviews near the end of his life he discussed myelodysplasia and said he was hopeful he’d been cured. He died at the Fred Hutchinson Cancer Research Center of pneumonia  after his third bone marrow transplant, a complication of this illness.

Most people with a diagnosis of MDS won’t have heard of it before. MDS is a group of bone marrow diseases. It’s at least as common as or more common than leukaemia but older people have a higher risk – perhaps one in 2,000 over the age of 60. A third of people with MDS will develop leukaemia. The 14th July, 2014, is the Leukaemia Foundation of Australia‘s second National MDS Day . One of the aims of MDS Day is to raise awareness of MDS.

Sagan’s illness was an opportunity to popularise MDS, but look how the cause of his death was described in these TV news reports.

In these news stories he was said to have died from a complication of “a rare blood disorder that led to cancer”, or “a blood disease”, “a bone marrow disease”, and even a” bone cancer” – the name of his disease was avoided.

Myelodysplasia literally means abnormal bone marrow cells. Blood cells are made in the bone marrow. In MDS the immature bone marow cells are abnormal and don’t mature properly. So the blood doesn’t have enough normal blood cells to do its job effectively. The blood is made of a number of different types of cells and the different types of MDS relate to the type of abnormal cell. MDS is often associated with a recognised chromosome abnormality, and identifying these chromosome abnormalities can help with diagnosis, treatment and prognosis. Therapy-related MDS is a specific type of MDS caused by treatment for a previous unrelated cancer and it usually has a poor outcome and very abnormal chromosomes.

MDS research has been neglected but has picked up recently. Some of the recent progress includes work by Carl Walkley and Louise Purton at St Vincent’s Institute in Melbourne, Australia.

MDS has had a history of name changes that seems to have made the meaning of its name less clear, except to medically trained people. This hasn’t helped improve public awareness of MDS. It was first named Di Guglielmo Syndrome in 1923 after its discoverer, then became refractory anaemia, then preleukaemic anaemia, preleukaemic acute human leukaemia, preleukaemia, and finally in 1976 the French-American-British Co-Operative Group of haematologists named it myelodysplastic syndromes. This recognised that it’s a group of related diseases and that not all cases will go on to develop into leukaemia.

Pathologist Ed Uthman, thinks Sagan’s Disease would be a better name for myelodysplastic syndromes – both as a tribute to Carl Sagan and a name that would mean more to most people than myelodysplastic syndromes.  Maybe he has something. Plenty of syndromes and diseases are named after people who studied them. Down Syndrome would have to be the best known example. Have you heard of amyotrophic lateral sclerosis? Motor neurone disease? Lou Gehrig’s disease? The first name is probably a nice technical description of the disease, but I’m guessing you’re more likely to  have an idea of what the disease is from one of the last two names, because they’re used in popular media and are connected in the public eye with famous sufferers – Stephen Hawking and Lou Gehrig. (Ed Uthman also think’s Lou Gehrig’s Disease should be “Hawking’s Disease”.)

I’ll let Carl Sagan have the last words on popular (mis)understanding of science (extract from Wikiquote).

We live in a society absolutely dependent on science and technology and yet have cleverly arranged things so that almost no one understands science and technology. That’s a clear prescription for disaster.

Every kid starts out as a natural-born scientist, and then we beat it out of them. A few trickle through the system with their wonder and enthusiasm for science intact.

(Cross-posted to Fireside Science at SciFund Challenge.)