Revealing the role of a fusion gene in leukaemia
What if we could identify the downstream effects of the gene fusion and the important pathways affected? Could this lead to potential new treatment targets?
Gene mutations are at the heart of many leukaemia cells. Understanding what these mutations do promises to unlock effective treatments with minimal side-effects. Dr Lisa Russell, Leukaemia UK John Goldman Fellow, has revealed the role of one particular mutation, which has big implications for leukaemia and other cancers.
Treatment for leukaemia has come a long way, but much of it is still based around chemotherapy. While these treatments are effective at killing cancer cells, they also affect normal cells and so cause side-effects that have a huge impact on people’s lives.
Discovering kinder and more effective treatments
One of the key aims for Leukaemia UK is to find treatments that have fewer side-effects. Understanding the biology of leukaemia is incredibly important to achieve this; if we can understand what makes a person’s cancer unique, we can identify the treatments that will work best for them. The hope is that giving the right drug at the right dose at the right time will provide them with a cure, while minimising the side-effects.
A key feature that defines a lot of leukaemias are gene mutations – changes to the DNA code. One group of mutations are known as ‘fusion genes’, when parts of two genes are joined together to form a new one. These are very common in leukaemia, such as the BCR-ABL1 fusion gene in chronic myeloid leukaemia, or ETV6-RUNX1 in childhood acute lymphoblastic leukaemia.
Studying the role of specific fusion genes in leukaemia is therefore crucial to understanding how that leukaemia develops and how the cancer cells multiply. Figuring out what the fusion gene is doing can provide new opportunities to develop kinder, more effective treatments.
Discovering a brand new fusion gene
Dr Lisa Russell leads a team at Newcastle University working to better understand fusion genes. During her PhD, Lisa studied mutations in a gene called CRLF2. She found that fusion genes involving CRLF2 could be found in acute lymphoblastic leukaemia (ALL), but that they weren’t enough to make normal cells turn into leukaemia cells. Another mutation was needed – another ‘genetic hit’.
Having discovered these rearrangements, I wanted to understand what else was going on in the genome of these patients, because we know that one genetic hit isn’t enough to generate the cancer.
Working with experts at the Sanger Institute near Cambridge, Lisa read the DNA code from samples donated by many people with acute lymphoblastic leukaemia. “And then this was where we found this novel fusion gene.”
The brand new fusion gene Lisa discovered is called USP9X-DDX3X, which is made by deleting a section of DNA between two genes, USP9X and DDX3X, joining them together. However, because no one else had studied the USP9X-DDX3X fusion gene before, there was very little information about what role it might be playing in ALL. So Lisa set out to find this out, with the help of a John Goldman Fellowship from Leukaemia UK.
Revealing the importance of the fusion gene
One of Lisa’s first tasks was to work out how common the USP9X-DDX3X fusion gene is among people with ALL. She found that among people with a mutated CRLF2 gene, 22% of them also had this fusion gene. But to her surprise, Lisa found the fusion gene is present in a lot of other people who didn’t have a CRLF2 mutation.
“It was a nice surprise”, Lisa says. “I think we only originally found it in two patients. You think, ‘is that the only two patients that we’re ever going to find it in?’. But when we started to look in more patient samples, it was nice to see it there too.”
Overall, this makes this fusion gene relatively common among people with ALL – which, to geneticists like Lisa, suggests this fusion gene must have an important role in leukaemia. Which begs the question: what exactly is this role? Lisa’s work would reveal an answer.
Understanding how cancer finds the right balance
Inside all cells, messages are being passed around, telling the cell what to do. The messages are transmitted along ‘signalling pathways’ – chains of proteins which pass the message along like a game of pass-the-parcel.
One of the most important signalling pathways in the cell is the JAK/STAT signalling pathway.
Activating the JAK/STAT pathway encourages the cell to grow and multiply in number. This is something that cancer cells exploit, through mutations or other changes which permanently activate the JAK/STAT pathway.
However, cancer cells can have too much of a good thing. Too much activation of the JAK/STAT signalling pathway can cause the cells to die, as if from exhaustion. So cancer has also found ways to control the signalling, turning down the volume so it doesn’t get too much. And it’s one of these control mechanisms that Lisa discovered.
The fusion of the USP9X and DDX3X genes inactivates both these genes. And Lisa found that this inactivation helps cancer cells control JAK/STAT signalling. The USP9X protein is normally an activator of JAK/STAT, and DDX3X controls how much of USP9X is made. Removing or reducing USP9X and DDX3X puts a limit on how much JAK/STAT signalling can be activated, keeping it at a level that the cancer cell is happy with. In essence, the USP9X-DDX3X fusion gene is helping the leukaemia grow in exactly the way it wants.
Better treatments and a good quality of life
It’s taken meticulous work over a long time to unpick how the USP9X-DDX3X fusion gene contributes to leukaemia. Understanding this opens new opportunities to find new treatments for people with ALL that carries this mutation. But the opportunities don’t stop there.
Lisa’s research also reveals new insights into how JAK/STAT signalling is controlled in cancer cells. JAK/STAT signalling is crucial in many leukaemia types, and also important in solid cancers too. So Lisa’s research could have an even wider impact as well. “It’s funny how one thing can lead you onto something else a bit bigger,” Lisa says.
There is lots more work to do in the lab before Lisa’s findings reach people with leukaemia. But the ultimate aim is to find new targeted treatments, to give more people the chance to be cured of their cancer, while maintaining a good quality of life.
Pushing the boundaries together
Lisa believes that the funding from Leukaemia UK was crucial in this research and in her career. The John Goldman Fellowship helped Lisa to create a research team and establish her research programme. And being a John Goldman Fellow has connected Lisa to a growing community of other scientists who are at similar stages in their career.
“As a Fellow, you can feel quite isolated. You’re meant to be working on your own research and proving that you can be independent,” Lisa says. “But actually, it’s nice to be surrounded by other people that are also making that scary step. It was nice to feel part of a family of Fellows at that time.”
Lisa believes that being connected to other researchers in this way bring big benefits to leukaemia research as a whole – and ultimately to people affected by the disease.
“In the past, people could probably do their research in isolation and that was sufficient,” she says. “But what we realise as scientists nowadays is that, because knowledge has moved on so much, we need to be collaborating and working with other people.
“We need to come together with other researchers in order for us to collectively push the boundaries of what we want to do – because we definitely can’t do that in isolation.”
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