Tackling chemotherapy resistance in T-cell ALL

Lead researcher - Dr Marc Mansour, University College London
Overcoming chemoresistance and discovering novel therapeutics for high risk T-cell acute lymphoblastic leukaemia
Amount awarded: £1,166,456
Award start date: 15 Mar 2014
Award duration: 5 years (60 months)

Although significant advances have been made in the treatment of T-cell acute lymphoblastic leukaemia, around 15% of paediatric and half of adult patients unfortunately succumb to their disease. We think that one of the reasons why leukaemia cells do not respond to chemotherapy is because they lose a gene called EZH2. EZH2 normally silences many other genes in T-cells – when EZH2 is lost or mutated, as it is in some aggressive leukaemias, these genes become continuously switched on. The question we have been trying to answer in the lab is which of the genes that gets switched on is the one responsible for resistance to chemotherapy. To this end, we have identified a gene called JDP2, which not only causes resistance to chemotherapy, but is also able to cause leukaemia itself. We plan to identify ways of drugging JDP2. We have also disrupted the EZH2 genes in zebrafish embryos, and will test several thousand drugs to find those that selectively kill the T-cells of fish that lack EZH2, but do not affect normal zebrafish T-cells. This way we can develop drugs that are lethal to leukaemia cells in high-risk patients, but with fewer side effects to the patient.