EHA 2015
Genomic sequencing to find AML-causing mutations
Dr George Vassiliou - Cambridge Cancer Centre, Cambridge, UK
I want to ask you about a kind of round-up talk that you’re giving here because it’s intriguing. Acute myeloid leukaemia, the molecular biology of the normal karyotype, now what are you addressing there, what’s the big issue?
The normal karyotype acute myeloid leukaemia represents about half of all acute myeloid leukaemia and we didn’t know a whole lot about it until the last six or seven years. A lot has come about as a result of new methods of sequencing DNA, as a result we found a whole lot of new genes that are involved in this disease. But also, and quite importantly, we found how this disease develops. We don’t know everything yet but we know quite a lot more about how it develops in normal people and then it can lurk in a pre-leukemic state and grow in some unfortunate people all the way towards leukaemia.
Is it acute myeloid leukaemia from the start or is it the same sort of cell?
Yes, essentially most leukaemias start in a stem cell, so a cell that is able to make other cells, make copies of itself and other cells. The stem cell is corrupted in a stepwise fashion by mutations in DNA and it often starts by moving towards a cell which can make more copies of itself. When that happens that means you have… the starting cell had a gene mutation, then you have a lot of copies of the starting cell so those copies they’re ripe to get a second mutation then they may get another new population etc. So this sort of serial corruption of the cell leads it towards leukaemia.
How can this understanding of the normal karyotype of AML help you with clinical decision making and guesses about which clinical approaches might be more optimal?
One very important forward step that has been made as a result of these advances is the fact that because the leukaemia has to evolve in this step-wise manner it doesn’t just evolve forward or linearly, it can also branch out. So when you have a leukaemia you usually have a whole lot of little branches of the leukaemia. So when you want to eliminate all of the leukaemia you have to find what all the branches have in common. Very often they have in common this gene that started the whole thing. These types, the specific genes that do that, we are much better at identifying them now. Future therapy has to focus on those genes rather than the genes that by and large come later on in the evolutionary process.
To summarise this particular topic, what kind of therapies would you put your money on for solving this initial genetic event, then, that might hit a number of leukaemia clones?
Essentially I think we need targeted therapies to either undo what a mutation does, in other words get in the way of the effects of the mutation, or, and this is another new method for identifying treatments now, the mutation changes the cell in a certain way then you go and find a vulnerability that comes about because of the mutation. So essentially the cancer developing mutation, it’s depending on a whole lot of the normal machinery of the cell and the cell next to it that’s completely normal is not. So you need to find those things and develop the treatments.
Any tips about what those things might be, typically?
Any tips? If I knew I would probably be trying them right now but we are trying to find the pathways. For example, there are a whole lot of pathways in metabolism that previously were not thought to be major players in leukaemia, they are now proving to be major players so drugs that affect cancer cell metabolism, drugs that affect how you process the RNA of cells, drugs that affect how the genes are switched on and off, the so-called epigenetic drugs, which are all coming in to the treatment.
