Archives for category: cell biology

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.

Mitosis has to be one of the more beautiful things in nature. It’s a choreographed dance of the chromosomes. It’s so small that we can’t see it without a microscope, but it goes on in our bodies billions of times a day.

DNA is a very long molecule made up of the genetic alphabet (which has four letters: A, C, G, T). A gene is made of a certain sequence of DNA letters (or bases) and spells out an instruction for a step in the complex workings of our bodies (such as the structure of insulin). The genes are strung together along the chromosome, and each cell has a set of chromosomes. For our bodies to grow, these cells need to make copies of themselves. The problem of how to distribute the copied chromosomes evenly to the two “daughter cells” is handled very elegantly.

 

Chromosomes arrested at mitosis and stained with Giemsa (unbanded).

Human metaphase chromosomes stained with Giemsa (unbanded). The two halves of each chromosome are copies of each other.

 

Mitosis is the solution. Mitosis is broken up into a series of phases: interphase, prophase, metaphase, anaphase, telophase. You could break prophase up further by adding prometaphase: the part of prophase between the nuclear membrane breaking down and metaphase (where the chromosomes line up at the metaphase plate).

Now follow the captions under the pictures.

The interphase nucleus - the DNA from all the chromosomes intertwined with each other is represented by grey modelling clay. (Actually it seems that the chromosomes stay in relatively distinct domains - but under the microscope they appear as one entity.)

The interphase nucleus.   The DNA from all the chromosomes, intermingled with each other, is represented by grey modelling clay. (Actually it seems that the chromosomes stay in relatively distinct domains – but under the microscope they appear as one entity.) The DNA in the interphase nucleus copies itself as the cell grows.

 

The DNA in the nucleus starts to package and take shape as prophase chromosomes.

The DNA in the nucleus starts to coil up in a pre-determined order and take shape as prophase chromosomes.

 

The DNA folds up in a pre-determined order to make recognisable chromosomes. When the cell is ready to divide each chromosome has two chromatids or identical halves, joined at the centromere.

The DNA folds up further to make recognisable chromosomes. When the cell is ready to divide each chromosome has two chromatids or identical halves, joined at the centromere.

 

At metaphase the chromosomes meet in the middle of the cell at the metaphase plate. Then as the cell divides to become two daughter cells, the two halves of the centromere split and travel along the microtubules in opposite directions, pulling the two halves of the chromosome behind them.

Metaphase - the chromosomes line up in the centre of the cell at the metaphase plate. They are attached by their centromeres to microtubules which stretch across the cell.

Metaphase – the chromosomes line up in the centre of the cell at the metaphase plate. They are attached by their centromeres to microtubules which stretch across the cell.

 

At anaphase the two chromatids (half chromosomes) become the new chromosomes as they separate and move in opposite directions along the microtubules.

At anaphase the two chromatids (half chromosomes) become the new chromosomes as they separate and move in opposite directions along the microtubules.

 

The chromosomes start to unravel to form the two new daughter interphase nuclei. The cell membrane (the outer covering) pinches at the centre and the one cell finally becomes two (cytokinesis).

The chromosomes start to uncoil to form the two new daughter nuclei – telophase. The cell membrane (the outer covering) pinches at the centre (cytokinesis).

 

The cell membrane pinches at the centre (cytokinesis) so the cell finally becomes two cells.

Cytokinesis finishes and we have two new cells in interphase.

 

If a chemical that destroys the microtubules is added to a laboratory culture, the chromosomes are stopped at metaphase. Cytogeneticists (chromosome scientists) use this technique to get enough metaphase chromosomes for analysis. Chromosome banding helps us recognise the chromosomes and identify any changes when an abnormality is suspected. Of course, the cell is also full of other organelles that have to be shared between the new cells.

The modelling clay images above are from my claymation showing mitosis. Modelling clay is a great medium for demonstrating and thinking about how things work, move and change. For the claymation I used a phone camera resting face down on a glass coffee table over the models.

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

Chromosomes that cause cancer. Part 2. The Philadelphia Chromosome.

This is a link to my latest post on the Fireside Science Blog on the SciFund Challenge website.

It describes the first discovery of a cancer-causing chromosome and the exciting progress in treating chronic myeloid leukaemia that it made possible.

The new Fireside Science blog at SciFund Challenge

I know, it’s been a long time between posts. I’m working on a breakage-fusion-bridge claymation to show how some cancer chromosomes are very changeable. It’s a steep learning curve but hopefully I’ll have it thoroughly mastered soon.

In the meantime here’s a post from Abby Buchwalter in the new group blog “Fireside Science” – SciFund Challenge’s Guide to Life, the Universe, and Everything. Abby and some of the other graduates of the first SciFund Challenge course (including myself) have started a group blog hosted by the SciFund Challenge website. Here we plan to bring the world of Science to readers in an easily digested form.

Abby describes a cell using only the 1,000 most common words in the English language.

Enjoy.