Scientists test potential new treatment for commonest form of infant leukaemia
3 October 2011
Mixed-lineage leukaemia is thought to account for up to eight out of ten cases of acute leukaemia in children below two years of age, and up to one in ten adult cases. Most patients do not respond well to standard leukaemia treatments and the cancer quickly comes back.
The disease is caused when a gene called MLL gets fused to another gene. This disrupts the normal function of MLL by creating a new 'fusion protein' that behaves inappropriately, switching on genes that drive the development of leukaemia.
The research team, based at the Wellcome Trust-Cancer Research UK Gurdon Institute and the Cambridge Institute for Medical Research at the University of Cambridge, collaborated with scientists from GlaxoSmithKline (GSK) and Cellzome AG to show that the MLL-fusion proteins are targeted to leukaemia-causing genes by proteins from the BET family, which recognise certain chemical 'tags' on chromatin, the scaffold on which DNA is organised.
In the study published in 'Nature', the researchers showed that a new chemical agent developed by GSK - I-BET151 - mimics these chemical tags, preventing BET and MLL from attaching to chromatin and activating the leukaemia genes. Treatment of leukaemia in mice and human cancer cells in the lab showed that the chemical could halt the disease, paving the way for its use in human trials.
Study co-leader Professor Tony Kouzarides, Deputy Director of the Gurdon Institute, said: "Our work shows that this type of leukaemia is reliant on MLL being able to bind to chromatin via BET proteins. This 'epigenetic' approach to therapy - which targets chromatin rather than DNA - is an exciting new avenue for drug discovery which we hope will be useful for other types of cancer in addition to mixed-lineage leukaemia."
Senior author Dr Mark Dawson from the Cambridge Institute for Medical Research, the inaugural Wellcome-Beit Fellow, said: "This is an exciting study with wider implications for cancer treatment as it highlights the importance of understanding how proteins mutated in cancer alter the chromatin landscape to initiate and drive cancer. It also demonstrates that treatments aimed at these proteins have great therapeutic potential."
Dr Brian Huntly, who co-led the study and is also based at the Cambridge Institute for Medical Research, said: "Mixed-lineage leukaemia is very hard to treat and often the only option for patients who have become resistant to standard treatments is a bone marrow transplant. We hope these findings may in future mean that fewer children need this procedure."
Image credit: Anthea Sieveking/Wellcome Images
Reference
Dawson M et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2 Oct 2011 [epub].
