Blood cancers

Dr Edward Chew: identifying the genes responsible for poor AML outcomes



Challenge: can you describe the aim of this project in 10 words?

Our aim is to understand how AML can become resistant to chemotherapy and return with a vengeance.

Why are you focusing on core-binding factor AML?

In general, outcomes in AMLs are poor. The dogma is that core-binding factor AMLs respond well to initial chemotherapy and have a “favourable” prognosis. Even within this subgroup however, the leukaemia can return.

Together with my PhD supervisors Professor Andrew Roberts and Dr Ian Majewski; and our collaborators Professor Terry Speed and Anna Quaglieri, we thought it would be interesting to find out why AMLs that were predicted to do well, ended up developing a resistance to chemotherapy.

If we can find out how and why core-binding factor AMLs become resistant to chemotherapy it would lead to the development of better predictive markers that we could use clinically. For example, we could identify patients who would benefit from other treatments, such as an early stem cell transplant. It would also reveal more about the biology of AMLs as a group.

What have you already discovered in this area?

Anna Quaglieri has developed the bioinformatics tools needed for our analysis. Specifically, she has shown how deep our RNA sequencing tests have to be – i.e. how many strands of RNA we need to sequence in order to obtain meaningful results. This gives us much confidence in our work moving forward and will save us money in the long run.

Second of all, we know that core-binding factor AMLs have either t(8;21) or inv(16) in their karyotype. From sequencing the RNA, we have proven that they are biologically very distinct. We always suspected this but we never expected how different their gene expression profiles are. They both started with mutations in genes from the core-binding factor complex but different genes have subsequently been activated.

What aspect of this current research excites you the most?

I am fascinated with how AMLs are such a wily opponent. It turns out they are not one disease but many different subtypes and each of them have learnt to resist therapy differently. We have seen this in the core-binding factor AML project and also in other AML projects in our group. The challenge is to better understand this. Hopefully it will lead to tailored therapy for individual patients.

How long before this work might impact clinical care?

Optimistically, three to five years. Once we have identified the biomarkers that predict resistance to chemotherapy, we will supplement this with other large publically available sequencing data sets. The goal is to use these biomarkers in a prospective clinical trial. At the same time, we would be interested in doing more basic science research with our findings – there’s a lot still to do!

What’s your research Holy Grail – the one thing you’d like to achieve in your career?

To discover how genetic mutations result in leukaemias. I am aware this is a lofty aim! In research, we stand on the shoulders of those before us. Every small bit adds to our body of knowledge and I would be happy if something I have worked on subsequently adds to a better understanding of leukaemias.

What is your biggest research hurdle right now?

Time and money. It feels like there is never enough time to do everything. Research is also costly and every little bit, like our recent grant from the RCPA and Illumina, and my scholarship from the Leukaemia Foundation helps.

Who has inspired you in work or life?

My grandparents – they always told me to be polite, encouraged me to pursue my studies and not to be afraid of hard work.

How do you manage work-life balance?

Poorly! It helps to have supportive family and friends who encourage me to have fun and stop me from being too serious.

Can you nominate a book that influenced you and why?

Contact by Carl Sagan. People remember Carl from his television series, Cosmos. For me, he was also a great writer – he used a science fiction novel to describe how real science worked and its possibilities. I read it at 17, it led me to other great science writing and here I am.

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