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.
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