Back in 1999, Julia Horsfield began working as a postdoctoral fellow in Professors Phil and Kathy Crosier’s laboratory at Auckland University. Her work involved using zebrafish – renowned for their transparent bodies and for sharing 70 per cent of our genetic code – as a model to find new genes involved in leukaemia.
Unbeknownst at the time, this HRC-funded project and the subsequent follow up study would lead to a surprise discovery that is today the major focus of leukaemia researchers worldwide.
In the first HRC-funded project, Julia – now an associate professor and head of her own laboratory at Otago University – created random mutations in the genetic material (genome) of the zebrafish to see how they affected a particular gene called RUNX1.
“The RUNX1 gene is commonly mutated in leukaemia, with even small changes in its amount predisposing a person to leukaemia. For this reason, it is one of the most common targets in childhood and adult leukaemia. However, mutations in RUNX1 alone can’t cause full-blown leukaemia – for that you need other genes to be mutated as well. We were hoping to find other genes in the genome that would cooperate with RUNX1 to progress leukaemia because this would be critical to designing new therapeutic approaches,” explains Julia.
And they did. By the end of their second HRC project grant, which finished in 2007, Julia and the team had put out a paper in the international journal Development showing for the first time that a gene called RAD21 could control RUNX1.
“Cohesins are proteins that make up the ‘glue’ that holds chromosomes together during cell division. At the time, RAD21 was known as being part of this big cohesin protein complex. However, there was no mention of RAD21 being involved in controlling genes or causing leukaemia,” says Julia.
“We were the first to reveal the role of cohesin in the expression of developmental genes.”
Since the Development paper, researchers have discovered that cohesin has a role in controlling the expression of a raft of other genes too, including those important for human development and cancer. With the advent of technology to sequence whole cancer genomes, it’s now known that about 13 per cent of people with acute myeloid leukaemia have cohesin mutations while a further 15 per cent don’t make enough cohesin for gene expression to occur.
A recent article in the New England Journal of Medicine re-categorised acute myloid leukaemias according to gene mutations; cohesin represented one important category of ‘driver’ mutations. The RAD21 mutation in particular co-occurred with mutations in RUNX1 in leukaemia, validating the HRC-funded observations made 10 years ago in zebrafish.
“The HRC can be proud that it funded this work as it was a very important piece of the jigsaw in leukaemia research. Cohesin is now a key focus of global research on acute myeloid leukaemia. It’s set us on the world stage for having discovered what we did when we did,” says Julia.
More than 10 years after making this unexpected discovery that changed the future direction of leukaemia research, Julia and her team have now come full circle with a new HRC grant. This time, they are testing if cohesin mutations cause acute myeloid leukaemia by leading to abnormal RUNX1 gene expression. They will also screen for drugs that selectively target cohesin-mutant leukaemia in both zebrafish and human cancer cells.
Julia says that her story is just one of many showing how early health research investment can go on to make a huge difference later on.
“Often research makes a difference in ways that you don’t expect it to at the time. If you could predict every outcome of your research, then why do it? I’m very grateful that the HRC took a gamble on this research because today’s successes are built on yesterday’s successes.”