Leukaemia Biology and Functional Genomics Laboratory

Functional Genomics of Leukaemia

We work very closely with clinicians to identify novel potential drivers of B cell cancers (in particular paediatric B-cell acute lymphoblastic leukaemia). In the laboratory, we then employ molecular biology tools including CRISPR-technology (CRISPR-Cas9, CRISPR-activation, Cas13) to model these lesions, often gene fusions, and determine their oncogenicity and response to targeted agents. Our studies ultimately help guide personalised medicine and can uncover novel mechanisms of leukaemogenesis or drug resistance.

Leukaemic intrinsic mechanisms of resistance to immunotherapies

Immunotherapies targeting the CD19 antigen (including CAR-T therapy) have become a promising therapeutic option for the treatment of relapsed/refractory B cell acute lymphoblastic leukaemia (B-ALL) and some lymphomas. Despite some remarkable success for these immunotherapies, up to 50% B-ALL patients will relapse. Using single-cell sequencing of matched diagnosis and relapsed samples, together with cutting edge whole genome CRISPR-screening these projects aim to identify leukaemic intrinsic mechanisms that may protect the leukaemic cells from immune-destruction.

The role of sub-clonal heterogeneity in leukaemia relapse

Our research has shown that B-ALL patients often have multiple competing subclones that evolve in response to chemotherapy. Despite existing only at a low frequency at diagnosis, subclones carrying RAS mutations often drive disease relapse. In the laboratory, we have developed novel models that allow us to mimic subclonal heterogeneity. With these, we are investigating how leukaemia cells evolve in the presence of other subclones, how they interplay with the bone marrow microenvironment, and how they can be therapeutically targeted to prevent relapse.