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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.

In the cells that make up your body, about 2 metres (6 feet) of DNA – strings of genes – are coiled up and packaged into a typically roundish nucleus. This nucleus is only about one hundred-thousandth of a metre wide. I’ve said before that the DNA packed into the nucleus “appears to be a tangled mess”. But looks can be deceptive.

In this great little video Carl Zimmer challenges the idea that DNA in the nucleus is arranged randomly. Job Dekker and his group are finding that the nucleus is actually very organised. Zimmer conjures up an image of tiny robots in the cell folding the DNA very precisely.

//players.brightcove.net/245991542/344c319b-6d23-4cbc-975e-c8530534af8a_default/index.html?videoId=4823709456001

[From Science Happens! Episode 5: Everything you thought you knew about the shape of DNA is wrong]

Some genes control other genes. Dekker’s research suggests that the way DNA folds helps this process – by bringing controlling genes close to the genes they regulate. One cause of cancer could be bad folding that interferes with this control mechanism.

Dekker’s group is trying to work out which genes lie next to each other and how DNA is folded. The answer will be extremely complex.  Dekker thinks that one day this knowledge will make it possible to fix badly folded DNA in cancer cells.

Cross-posted to Fireside Science on the SciFund Challenge network.

The 14th July is the Leukaemia Foundation of Australia’s annual National MDS Day.

Myelodysplastic Syndromes (MDS) make up a group of diseases that have abnormal blood cell production. MDS is sometimes called pre-leukemia because about a third of patients with MDS will develop leukemia.

MDS is caused by errors in the bone marrow’s genetic information. These errors can often be seen down the microscope as changes to the chromosomes. MDS patients typically have their bone marrow cells analysed to find chromosome abnormalities. Why?

These chromosome abnormalities can reveal important information about their disease, such as diagnosis, appropriate treatment and prognosis.

The IPSS-R is a system that’s used to work out prognosis for MDS patients – that is, how they will do – what their health outlook and risk of developing leukaemia are. A prognostic score is a number calculated from different aspects of the disease. A low score indicates low risk and risk increases as the score goes up. Cytogenetics, or chromosome analysis, is needed to calculate this score because “chromosome abnormalities” is one of the five categories used in the calculation.

For example, if the cells are missing a Y chromosome nothing is added to the IPSS-R prognostic score, whereas if four or more chromosome abnormalities are found, 4 points are added to the score, which can almost single-handedly take the disease into the high (4.5-6) or very high (over 6) risk category.

del20q

Normal chromosome 20 (left) and abnormal chromosome 20 missing most of the long arm (“del(20q)”).

 

The abnormal chromosome pictured on the right is a deleted chromosome 20  – it’s lost a big chunk carrying hundreds of genes. This is one of the well-known chromosome abnormalities in MDS. We can work out which genes have been lost using higher resolution molecular analysis, but this is not necessary for calculating the IPSS-R prognostic score. One point is added to the score if there’s a deleted chromosome 20 and it’s the only chromosome abnormality. It’s one of the chromosome abnormalities in the “good” cytogenetic category.

So chromosome analysis is an important piece of the puzzle in the care of MDS patients.

More information:

The IPSS-R http://www.bloodjournal.org/content/120/12/2454?sso-checked=true

MDS Foundation – What is MDS? http://www.mds-foundation.org/what-is-mds/

The MDS Beacon http://www.mdsbeacon.com/

Previous MDS Day posts:

Carl Sagan’s Lasts Project – Overcoming MDS

MDS and the Fantastic Mr Dahl

What does IPSS-R stand for? Revised International Prognostic Scoring System for Myelodysplastic Syndromes.

Cross-posted to Fireside Science on the SciFund Challenge network

 

 

The Leukaemia Project has a new home on this blog. It features my research, and most particularly Elizabeth Duong’s short film about Sadako Sasaki and the thousand paper cranes. You can read about the making of the film on some of the earlier posts and watch it here:

and here:

This is a nice summary of the Research Bazaar conference held in Melbourne last week. We learnt various programming languages and did other researchy-type things. This was the first ResBaz but I think it was so successful there’ll be more. Read more about it here!

Rosanna's Research

ResBaz, or Research Bazaar, was hosted this year for the first time at the University of Melbourne and I got to attend this awesome conference (so did a couple of other QAECOlogists, check Saras Windecker’s blogpst for an impression). ResBaz is all about open science, sharing, collaborating and getting the message out there. To make this happen, the attending researchers were trained in digital tools such as R, MATLAB, Phython, mapping software and version control.

I only attended two streams, R and SQL (databases), but because of all the mingling with fellow researchers under the big bazaar tent (as well as twittering, lots of twittering!), I also got a good impression of all the other great stuff that’s out there. I have to say, it’s good to know what all the options are when doing your research. If you missed the conference, here’s a list of all the cool…

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The WordPress.com stats helper monkeys prepared a 2014 annual report for this blog.

Here’s an excerpt:

A San Francisco cable car holds 60 people. This blog was viewed about 2,000 times in 2014. If it were a cable car, it would take about 33 trips to carry that many people.

Click here to see the complete report.

On the 9th of December there was a large oil spill in the Sundarbans of Bangladesh. Most of the 350,000 litres of furnace oil in an oil tanker spilt into the water. Check out these images from the BBC.

The Sundarbans in Bangladesh is the world’s largest contiguous tidal mangrove forest. The mangrove ecosystem is ecologically valuable, filtering contaminants out of the water. Mangroves are already threatened around the world. The Sundarbans is noted for its exceptional biodiversity but the oil spill is threatening many unique species including the Bengal tiger and the Ganges river dolphin. And mangroves are particularly sensitive to oil spills.

 

There’s also a huge human cost. The locals are not in the lucky position of having a government with money and technology to help clean up the mess. They’re scooping the oil out of the water with their bare hands. This oil is toxic and cancerous. Its components cause severe (poor prognosis) leukaemia. Children are exposing themselves. They need our help.

I’ve found a bit of news coverage online, but little from Australia’s government sponsored news broadcasters. There’s nothing from SBS (our overseas-focussed broadcaster), and only the one story from our ABC. This environmental disaster affects us not only because of the damage to a UNESCO World Heritage Site and the threat to wildlife, but also because the water in the Sundarbans is everyone’s water – it reaches your country in a manner of days. If the media won’t cover the story you can help play a crucial role. Pester the news media. Spread the story on social media.

Here are some tips on how to do this:

From Water Defense:

“Share information about the oil spill on your social media page to keep it top of mind. For the latest information check on Twitter @Sundarbans_SOS for regular updates and remember to use the hashtag #SundarbansOilSpill.”

From the River Dolphin blog:

“If this post bothers you at all, then I suggest you 1) contact major forms of news media (see post one for how to if you are in the US) and work HARD to get them to cover this story (US still not covering for the most part). 2) Write to the leaders of your country and ask them to pressure the government of Bangladesh to change this clean up solution IMMEDIATELY.  3) SHARE (don’t like… only sharing moves this story along) this post, and help us get the word out.”

An international response team including oil spill experts has now been sent to the Sundarbans in response to a request to the UN from the government of Bangladesh.

There’s an indiegogo campaign to raise money to get extra help to the Sundarbans – the not-for-profit Water Defense organisation wants to send a team to help clean the water. Why donate if there’s a UN team? Besides the obvious statement that a faster cleanup is better, there’s some controversy about using chemical dispersants to clean up oil spills. These dispersants end up in the water. The Water Defense team has a specially developed water cleaning foam that soaks the oil out of the water.

 

Follow Jennifer Lewis’s River Dolphin blog. Jennifer is the Director of the Tropical Dolphin Research Foundation. She reports on the human impact of the oil spill.

http://theriverdolphin.blogspot.com.au/

http://theriverdolphin.blogspot.com.au/2014/12/side-track-off-dolphins-for-one-post.html

http://theriverdolphin.blogspot.com.au/2014/12/ecological-disasterto-say-least.html

http://theriverdolphin.blogspot.com.au/2014/12/assessing-damage.html

 

More information:

http://news.nationalgeographic.com/news/2014/12/141216-sundarbans-oil-spill-bangladesh-tigers-dolphins-conservation/

http://news.sciencemag.org/asiapacific/2014/12/officials-scramble-respond-bangladesh-oil-spill

http://www.theguardian.com/environment/2014/dec/11/bangladesh-oil-spill-threatens-rare-dolphins

http://thinkprogress.org/climate/2014/12/24/3606793/experts-to-help-children-clean-mangrove-oil-spill/

http://whc.unesco.org/en/news/1209

http://en.wikipedia.org/wiki/List_of_oil_spills