Master regulators
Assoc Prof Ng has spent over a decade researching a protein that regulates gene activity in the cell nucleus, known as ERG. Imbalances in this protein can lead to blood cancers, like acute lymphoblastic leukaemia.
His previous research uncovered the protein’s critical role in Down syndrome associated blood disease and normal blood cell function, including how B cells – which are essential for producing antibodies to fight against infections – develop.
First author Dr Kira Behrens said the research team wanted to understand what other types of proteins ERG works with to fuel leukaemia development.
“We looked at the proteins that control how specific genes switch ‘on’ or ‘off’ to analyse how normal B-cells – and critically – B-cell acute lymphoblastic leukaemia – can develop”, Dr Behrens said.
“After analysing the genes regulated by ERG and another protein, c-MYC, we discovered that these proteins were actually the master regulators of several important pathways and processes within the leukaemia cell.”
Researchers then narrowed the list down to focus on one pathway essential for making proteins, known as ribosome biogenesis.
This led the team to focus on targeting a key gene essential to this pathway, POL I, which is also controlled by these master regulator proteins.
The gene helps direct an important cell growth and division process that can lead to the development of cancer if it goes awry.
Dr Behrens said: “By targeting POL I with inhibitors, we were able to kill leukaemia cells and stop their growth in our pre-clinical and human tissue models.”
“This was a surprising, yet remarkable discovery, as we were able to unravel a new pathway and potential drug target that can hopefully be used in the fight against leukaemia in the future.”
The study also involved a collaboration with Associate Professor Elaine Sanij (St. Vincent’s Institute of Medical Research) whose work focuses on targeting POL I and ribosome biogenesis in cancer therapy.
“The findings show that a subset of aggressive acute lymphoblastic leukaemia exhibit a form of addiction to producing of ribosomes, the protein making molecular machinery,” Assoc Prof Sanij said.
“They render this aggressive leukaemia sensitive to POL I inhibitors which target ribosome production.
“Altogether, our work highlights the importance of developing this new approach to cancer therapy to treat oncogene-driven cancers.”
