Epigenetics and Cancer

11 December 2012

Interview with

Mark Dawson, Cambridge University

Apart from enabling us to understand how cells function and develop normally, epigenetics can also give us some new treatments for a range of diseases including cancers and Haematologist Dr. Mark Dawson from Cambridge University works on this very question. 

Chris - I presume your case Mark, it's chiefly going to be diseases or cancers of the blood, leukaemia, is that you're interested in?

Mark: -   That's right.  I spent part of my time at Addenbrooke's Hospital caring for patients with various types of blood cancers including leukaemia as you just said.

Chris: -   Which type?  You've done some pretty instrumental studies looking at the role of epigenetics in these leukaemias.  Which ones were you looking at in particular because they're quite a big family of diseases?

Mark: -   Broadly speaking, my research interest is about white blood cellsthe acute leukaemias.  So, these leukaemias are cancers of white blood cells, and somewhere between 5 to 8-10 people per 100,000 of the population develop an acute leukaemia. 

What's sad about this disease is that despite progress in modern medicine and supportive care, we've made very little progress in trying to cure the vast majority of these patients.  In our current therapy, only less than 30% of these patients actually get cured.

Chris: -   When we look back over the history of treating leukaemias though, once upon a time, we just knew people had some kind of disease that made them have enormous numbers of the wrong sort of white blood cells in their blood, and we knew that they got sick and we knew that giving them drugs that were horrendous but killed off those cells since to make them live longer.  Now, we understand quite a bit about what's going on genetically about these disorders.

Mark: -   That's right.  So now, if you take acute leukaemia for instance, we know in over half of these patients what the initiating event is.  So, this is a genetic abnormality that is called a chromosomal translocation.  And what happens here is that part of a chromosome breaks off and fuses abnormally to a completely different chromosome.  What this results in is the fusion of genes from two different chromosomes together.

Chris: -   So if I had say, chromosome  number 1 and a chunk of fell off there, it could take itself to chromosome  number 2 and stick itself on instead of the equivalent chunk of chromosome  number 2.  Where the two joined, I've now got two sections of genetic material linked together, and I've effectively made a new gene by linking that chunk of chromosome to the other chromosome.

Mark: -   That's exactly right.  These are called fusion genes and they're only really present in the cancerous cells.  So, none of our normal cells whilst they have two original copies of what these genes are.  They don't have the fusion together.

Chris: -   And what do those fusion genes do?

Mark: -   The vast majority of them serve to initiate or drive the process of leukaemia and the fusions I've been studying more recently are called the MLL fusions.  So here, one part of this fusion is a gene is called the MLL gene and this produces a protein related to the proteins that you and Stefanie have just been talking about, an epigenetic regulator.  And what it does is it binds very specifically to a small set of genes and it modifies them by laying down a chemical group on the histone protein surrounding these genes.  And what this modification does is really prepare this gene to be turned on.  So the MLL gene is involved in the initiation of gene expression.

Chris: -   So, there's a normal gene there whose job it is to go to a certain part of the DNA of a cell and say, "Right, you are going to turn on and your gene is going to be expressed."  So when we then take that gene and fuse it to another gene, making this funny fusion, it retains the ability to address itself to different bits of the genome, does it?

Mark: -   Exactly.  Its targeting potential is still preserved.

Chris: -   What else happens beside that?

Mark: -   So, what happens is what we've realised more recently is many of the fusions that the MLL genes stuck towards - the other genes - are also genes that code for proteins that are involved in the process of gene expression.  But these proteins really continue the process of gene expression and are involved in the completion of gene expression.  So, what these fusions eventually do is they form this sort of turbo charged driver of gene expression.  It increases the expression of several of the MLL target genes, but also increases the expression of genes that should normally be turned off at this stage.

Chris: -   So, you end up with this fusion protein, taking a very potent turn on signal for genes to lots of different places in the genome that wouldn't normally get turned on like that.

Mark: -   Correct.

Chris: -   And that starts the cells dividing and growing in this abnormal cancerous way.

Mark: -   That's right.  Many of these genes that are turned on in this way actually confer upon these cancerous cells a survival and growth advantage, and that's eventually what leads to the process of leukaemia.

Chris: -   Begging the question, now you know that, could you intervene and interrupt the ability of that funny protein to address itself to all these different places in the genome and turn it off?

Mark: -   Yes, so that's exactly what we've been studying.  We've been trying to understand.  What's clear is that these fusion proteins don't work in isolation.  They work with a number of collaborators.  Other proteins, they perform as what we call a protein complex and each component of this protein complex plays an important role in the regulation of this gene expression. 

We looked very deeply to understand what are the components of the MLL fusion protein complex and we found that there are part of this complex that contain a group of proteins whose job it is to anchor the MLL fusions at these specific genes.  They do so by using a special binding module that recognises a chemical group on the histone proteins.  So, binds this and locks on there and keeps the whole protein complex there.

Chris: -   So, you've understood what the molecular Velcro is that sticks this strong expresser of genes to the wrong bits of the genome. So have you got some way of interrupting that process?

Mark -   That's right.  So in collaboration with GSK, a pharmaceutical company, we've developed a molecular decoy so to speak.  This small molecule largely mimics the chemical modification that we see on the histones.  And so, this works as a decoy to draw away the protein complex from being locked on to the genes to away from the genes, and then now, the genes can actually be turned off.

Chris -   Was this in mice or people?

Mark -   So, we use this in a number of different studies, a number of laboratory models of leukaemia, including studying cells and how they grow in a dish, what genes they turn on and turn off, and how this small molecule turns these genes off.  We also were able to show very successfully in models of leukaemia, mouse models of leukaemia, that this small molecule really confers an impressive therapeutic advantage for these mice.

Chris -   Are you doing this in humans now?

Mark -   So, based on our study and other studies from around the world, phase I clinical trials with this compound in patients with cancer have already started in the US, and we're hoping that this will follow on and be rolled out to the UK, where some of our patients can be involved.

Chris -   I suppose it's relevant with David Cameron saying he wants everyone to be in a human DNA database across the country and marry that data to our medical records.  But this, I suppose we should emphasise is one particular kind of leukaemia, and you've had to do this sort of DNA detective story to work out how this disease occurs.  We couldn't just assume that the same compound is going to work in a range of other diseases because they're going to have a different process, aren't they?

Mark -   That's exactly right and we know that is true for this compound.  It works in a very specific subset of cancers, leukaemia being one of those cancers, but it's not a panacea for cancer.  So, it's not likely that this will be what we've been looking for to cure all cancers because different cancers are driven by very different genetic events.

Chris -   Mark, thank you.  Mark Dawson from Cambridge University.

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