A/Prof Ross Dickins' group works on
genetic mutation in cancer
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Whereas about 90% of paediatric ALL patients can be cured with current therapies, the prognosis for those who don’t respond is poor.
Monash University researchers at the Australian Centre for Blood Diseases (ACBD) used a novel approach to identify three genes that could be potential new targets for drugs to treat these patients.
Past research in leukaemia has established that patients with high-risk disease often harbour mutations that disable a transcription factor called IKAROS, which normally suppresses tumours by controlling the activity of hundreds of other genes.
For several years the laboratory of ACBD researcher Associate Professor Ross Dickins has investigated exactly which genes are regulated by IKAROS in ALL – a needle-in-the-haystack search had it not been for a novel strategy.
Using unique genetically engineered ALL mouse models the researchers switched IKAROS on and off to identify genes regulated by it in mouse leukaemias, then compared this list with genes identified by researchers working on human ALL in the Netherlands and at St Jude Children’s Research Hospital in Memphis.
Combining the mouse and human lists allowed the researchers to narrow down those genes responsible for the disease.
Associate Professor Dickins said his team then focused on three of these interesting genes, looking at them in greater detail.
“This paper has identified several genes that can now be investigated by the field as potential drug targets in high risk disease,” he said. “Generating several new data sets and combining their analysis has given us strong statistical confidence in these genes.”
The ACBD researchers were delighted to find that two of the three genes newly associated with IKAROS mutations had previously been implicated in ALL treatment response in the literature, adding strength to their findings. The third, CTNND1, was a novel target.
Remarkably, the researchers also found that restoring the function of IKAROS in an established tumour caused it to rapidly disappear. “That was a surprise – it was pretty cool,” Associate Professor Dickins said.
Dr Matthew Witkowski, now doing post-doctoral research at New York University, is first author on the paper.
Witkowski MT, Hu Y, Roberts KG, Boer JM, McKenzie MD, Liu GJ, Le Grice OD, Tremblay CS, Ghisi M, Willson TA, Horstmann MA, Aifantis I, Cimmino L, Frietze S, den Boer ML, Mullighan CG, Smyth GK, Dickins RA. Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. J Exp Med. 2017 Mar 6;214(3):773-791. doi: 10.1084/jem.20160048. Epub 2017 Feb 11.