EHA 2015

Exploring "bad luck" - why do some patients develop myeloid leukaemia?

Dr George Vassiliou - Cambridge Cancer Centre, Cambridge, UK

You have been discovering mutations in normal people that could potentially become leukaemia. Enlighten me what this is all about.

We and others have described this phenomenon of some of the mutations that you find in a fully-formed leukaemia you find them in normal people. This is a phenomenon that increases with age and it’s almost certainly because during our lifetime our cells get mutations. If after a certain number of years we get a mutation that can give this growth phenotype, let’s say, to a cell, the cell will outgrow the other cells then, as I mentioned earlier, that cell can go on to develop leukaemia. But you still need to be unlucky because this phenomenon we described is very, very common, the majority of people over 90 will have this start of the leukaemogenic process but only a small minority will go all the way to leukaemia.

Now you can have the growth phenotype but it might not be expressed, what are the factors holding it in check?

Essentially if we go back a step, before you had this mutation the body is controlling the growth of its cells, of its own cells. So one cell gets a little bit out of control, the body is again sort of able to control it but not quite as well. That cell needs more mutations to get to leukaemia and what we have found is that leukaemia is a disease, acute myeloid leukaemia that is, of bad luck. So there has to be more bad luck to get more mutations with the passage of time. If we did live hundreds of years then bad luck may not come into it because by then we’d all get leukaemia. But, given our lifespan, we have to be unlucky to get all those mutations in our lifespan to get leukaemia.

And how does age come into this equation?

Age, simply the passage of time, allows mutations to build up in the body and that’s the major role of age.

And the therapeutic potential opportunities coming out of all of this knowledge?

Again, one important observation that was made by us and others is the fact that some mutations appear to be particularly present in old people with normal blood tests and not in young people. We think that this phenomenon is hinting at the fact that the environment in the body is changing with old age or with aging, and the cells can exploit that to grow. If we find what that change is in the environment, again it may be a very innovative and new way to tackle leukaemia that has not been exploited so much in the past.

But you haven’t sussed out the environmental factors yet?

No, but we are working on them.

The evolution of leukaemia and the fact that you can start with one type of cell that can perhaps progress, what is known about that and how might that give doctors an ‘in’ to new treatments?

Again, it’s all related to what we were discussing but because the leukaemia evolves, just like organisms evolve in nature, it exploits its environment. So if we talk about a normal environment, a young, fit person, there are some mutations that can outgrow the controls in a normal fit person but in an older person the environment is different, subtly different, sometimes significantly different, so the changes in the leukemic cell can exploit that environment. So if we understand that environment is important, just as it is nature, it is also important in the evolution of cancer. Because evolution can be, as I mentioned, forward and sideways we need to know a leukaemia is a complex entity. It’s not just a single clone of cells coming from a single cell.

Let me ask you about the signature of mutagens because I gather that there are both internal endogenous mutagens and exogenous factors that can cause this whole process and stoke the fires of leukaemia. What are they, what have you discovered so far?

Well, my colleagues, Professor Mike Stratton of the Sanger Institute and Dr Nik-Zainal who is a group leader there and Ludmil Alexandrov who was previously a PhD student there, they have really worked very hard in this field and they have revealed something quite fundamental to cancer – that if you look carefully in the sequence of cancer you can find particular DNA changes called signatures. Those signatures are often attributable to particular mutagens, for example tobacco has its signature, certain viruses may have a signature, certain chemotherapies can have that signature. You don’t need to know the person had the chemotherapy, you can almost look at the DNA and infer that. Additionally, endogenous processes that are ongoing at a slow rate in our body have their own signature and that’s why aging has that particular signature of those endogenous processes.

So finally what is this telling cancer doctors, do you think?

What it is telling us is how some cancers develop that we had no idea about what drives these cancers, what causes these cancers. We are beginning to understand what causes them and we are beginning, potentially, to think of ways to prevent them from occurring.