CRUK Senior Clinical Research Fellow
Description of research
Chronic lymphocytic leukaemia (CLL) is an incurable disease derived from mature B cells and characterised by a profound defect in programmed cell death. The goal of our work is to understand how signalling pathways become activated in CLL cells by intrinsic mutations and extrinsic signals from the microenvironment. Since CLL shares many clinical and biological properties of other low grade B cell non-Hodgkin lymphoma (NHL), our findings potentially have implications for the treatment of other B cell malignancies.
There is growing evidence indicating that the survival of tumour cells is not cell autonomous, but highly dependent on survival signals provided by bystander cells in the microenvironment. Results from our lab demonstrate that malignant B cells actively reprogram cells of their microenvironment, thereby creating an inflammatory niche, which is essential for the survival of malignant B cells. Interference with this activation completely ablates the propagation of B cell lymphoma in a mouse model, indicating that targeting the microenvironment instead of tumour cells is a very potent treatment approach. In particular, we now seek to understand (1) how cells of the microenvironment become activated and (2) which kinases are required to activate NF-kappaB in bone marrow derived stromal cells.
Related to these questions, we want to define how lymphoma-intrinsic mutations specifically affect the dependency of lymphoma cells on their microenvironment, considering the growing complexity of mutations throughout clonal evolution of B cell malignancies.
Another focus of the lab is the receptor associated tyrosine kinase ZAP70. Its aberrant expression in CLL is indicative of a poor prognosis, but little is understood how it contributes to the pathogenesis of CLL or other B cell lymphomas.
Since we intend to translate our findings into clinically applicable therapies, much of our experimental work is done with primary cells from patients, complemented by in vitro and in vivo disease models/co-culture systems. Our work benefits from strong local collaborations in Cambridge and international collaborators.
Keywords: Microenvironment, B cell malignancies, kinases
Clinical conditions: CLL and low grade B cell lymphomas
Methodologies: Mouse models of B cell lymphoma, in vitro (mouse and human) co-culture models