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Emma Williams, a PhD student in Dr Tim Somervailles’s lab at the Cancer Research UK Manchester Institute, writes about the team’s latest discovery.
It’s not just forensic teams that solve mysteries with science. Cancer researchers do too. Today, our team’s latest investigation has been published in the journal Cancer Cell – we’ve solved the mystery of why a gene involved in the development of the human eye may also play a role in an aggressive form of blood cancer.
When we talk about genes ‘for’ particular organs we mean the bits of DNA that are switched on inside cells in that organ.
These genes play a fundamental role in helping a cell specialise in doing a particular job.
But we found a particular eye gene, called FOXC1, that is switched on in around one in five patients with a type of blood cancer called acute myeloid leukaemia (AML). And, being an ‘eye’ gene, you may have guessed that this is a bit strange.
It turns out that FOXC1 acts as a ‘partner in crime’ with another, known leukaemia gene, called HOXA9. And our research has shown that together, these genes might be behind more aggressive cases of AML.
So how do these two genes collude to make this particular type of blood cancer more aggressive?
And, most importantly, how might this allow us to look for new ways of tackling the disease?
Human instruction manual mix-up
Finding FOXC1 in blood cells is an example of a gene being active in the wrong place at the wrong time.
All of the cells in our body carry a genetic instruction manual to build an entire human being. The way cells gain an identity – for example as an eye cell or blood cell – is to only use certain chapters of their instruction manual. These chapters contain all the words that tell the cells what to do and how to behave. And these words are what we know as genes.
The selection of chapters used by cells is very tightly controlled. And it’s very important that cells use the right chapters and genes at the right times.
So you can imagine our surprise when we found that some leukaemia cells were reading from a chapter normally used to build solid organs, like the eye, bone and kidneys, as a foetus grows in the womb.
This was our first clue. We already know that cancer can arise and spread due to identity mix-ups when cells use the wrong pages of their manual. For example, when ‘bone’ genes are switched on in breast cancer cells that have spread to the bone.
Our next step was to investigate what FOXC1 is doing in leukaemia cells, and if it can contribute to how blood cancer develops.
Acute myeloid leukaemia
Our study focused on acute myeloid leukaemia, a cancer of blood cells which affects around 3000 people per year in the UK. This leukaemia gets its name because it develops quickly (hence ‘acute’) and comes from one of the two groups of blood cells, called myeloid cells.
In normal blood production, blood stem cells specialise into all the different types of mature blood cells to help the blood work. For example, the myeloid group includes oxygen-carriers (red blood cells), blood-clotters (platelets) and some infection-fighters (white blood cells).
In AML, this process of specialisation is faulty. The patient’s blood and bone marrow become overrun with immature, non-specialised cells we call ‘blast’ cells, causing symptoms like a drop in the number of red blood cells (anaemia) and susceptibility to infections.
While a lot of progress has been made in treating some types of leukaemia, treatment for AML has developed very little in over 40 years. So Cancer Research UK scientists like us are trying to better understand the disease to find new drug targets. In particular, we want to find drugs that can restore the way cells develop and specialise, and make the blast cells healthy.
Scientists and doctors are also keen to know why some patients’ AML is more aggressive than others, because these differences could have important implications for how the disease is treated.
So where does FOXC1 come into this?
Eye and leukaemia genes are ‘partners in crime’
The clue which kicked off our investigation was the discovery that FOXC1 is wrongly switched on in around one in five AML patients.
Next, we dug deeper to figure out what effects the FOXC1 gene has when it is switched on in leukaemia cells.
We carried out experiments where we grew AML cells in the lab and stopped them from switching on the FOXC1 gene. Without FOXC1, the AML cells started to specialise like normal cells would, and in some cases they also stopped growing. We then showed that FOXC1 can also block blood cell specialisation when we artificially switched it on in normal, healthy blood stem cells.
This told us that FOXC1 can play an important role in the blood cell specialisation block that is responsible for AML.
But we also found that FOXC1 can’t cause leukaemia on its own. Instead, it needs a partner in crime – a known leukaemia-causing gene called HOXA9, which AML cells often produce large amounts of. HOXA9 helps to keep healthy blood stem cells ‘young’ and unspecialised, but too much of this gene is a key culprit in the AML specialisation block.
Once we knew that FOXC1 and HOXA9 were linked, we were able to show that they act together to block blood cell specialisation, and speed up leukaemia progression in mice.
This evidence suggests that high FOXC1 levels are associated with poorer survival in people with AML, and when we examined real patient data, we found this to be true. This has also been shown for some solid tumours, like breast and liver cancer.
The next big question is whether we can turn these findings into a potential treatment to target these genes. Switching off genes in real patients is much harder than in cells grown in the lab, and because of the way that they work, targeting FOXC1 or HOXA9 with drugs is a challenge.
This is because FOXC1 and HOXA9 are from a family of genes called transcription factors – molecules that help to read the genetic code in our DNA. They are infamous among scientists for being tricky to target with drugs. This is because – unlike the more well-known enzymes targeted with precision medicines – they don’t have an ‘engine’ we can easily disable with drugs.
A key focus of our lab now is to figure out how FOXC1 is switched on when it shouldn’t be, and what other molecules are involved. We hope that our further detective work will reveal the identity of a more ‘druggable’ culprit.
For now, this study could provide a new tool for doctors to predict which patients have more aggressive forms of the disease. This in turn would help make some decisions about treatment a little less of a mystery.
Somerville, T., et al. (2015) Frequent Derepression of the Mesenchymal Transcription Factor Gene FOXC1 in Acute Myeloid Leukemia. Cancer Cell. DOI: 10.1016/j.ccell.2015.07.017
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