Exploring clonal diversity in paediatric B-cell leukaemia to identify new therapeutic weakness

Investigators: Sebastien Malinge, Rishi Kotecha, Laurence Cheung, Denise Anderson, Timo Lassmann

Collaborators: Thomas Mercher (Gustav Roussy Institute, France), Jean-Pierre Bourquin (University Children's Hospital Zurich, Switzerland), John Crispino (Northwestern University, USA), Ryan Lister (University of Western Australia), Alistair Forrest (Harry Perkins Institute of Medical Research Inc), Thierry Besson (Rouen University, France)

Partners: Children's Leukemia & Cancer Research Foundation (Inc.), Lejeune Foundation

Summary: B-cell acute lymphoblastic leukaemia (B-ALL) is the most common type of cancer seen in children. In recent decades, the survival of children with B-ALL has significantly improved with risk-adapted therapy, but many children still continue to suffer from treatment-related toxicity and relapse. Our aim is to identify which cancer cells are resistant to treatment by using models we have established in the laboratory. Understanding the behaviour of every single leukaemia cell in reponse to therapy will allow us to develop new drug therapies and monitor their efficacy in destroying resistant cells. The outcome of our project is to provide new tools to help clinicians identify treatment resistant cells , to better predict and prevent relapses, with a view to improving the care and well-being of children with B-ALL.

Description: 

B-cell acute lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy, accounting for 80% of all paediatric ALL. While five-year overall survival currently exceeds 90% with modern protocols, a subset of patients are refractory to treatment, suffer complications such as treatment-related toxicity and/or will develop relapse, which can lead to increased mortality and necessitate longer hospital admissions and ongoing care. There is also a dismal prognosis for patients who relapse (overall survival of only 30%). These features are exemplified in B-ALL in children with Down syndrome (DS-ALL). Children with DS-ALL have a 3-fold higher likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse compared to other children with B-ALL. Therefore, there is limited ability to use intensive chemotherapy protocols for these children. Characterisation of therapy-resistant clones from which relapses originate and integration of novel drugs targeting these clones into clinical trials is necessary to improve the long term outcome for children with DS-ALL.

This project aims to identify the leukaemia cells that are resistant to treatment and assess the therapeutic value of targeting the mechanisms altered by chromosomal abnormalities such as gain of chromosome 21 (+21). Using cutting-edge technologies (next generation sequencing, CYTOF, CRISPR/Cas9, in vivo imaging, single cell approaches), this project will focus on understanding the clonal response to conventional therapy, at a single cell level, to develop new strategies targeting the leukaemia cells resistant to treatment. This will open new avenues to improve long term outcomes for children with acute leukaemia.