Mechanisms responsible for the initiation and progression of CLL
The Molecular Lymphopoiesis group was established in 2005. We initially focused our research effort on investigating the molecular events that regulate lymphocyte lineage commitment and development. While investigating the role of PKCalpha (PKCα) in early lymphocyte development, we established that subversion of PKCα signalling acts as an oncogenic trigger in B lymphocytes, resulting in the development of chronic lymphocytic leukaemia (CLL). This finding resulted in a change in research focus for the group from lymphocyte development towards translational CLL research.
CLL is the most common adult leukaemia in the Western world with around 3,000 diagnoses in the UK per year, and there is currently no chemotherapeutic cure. The tumour microenvironment within lymphoid organs of CLL patients plays a pivotal role in promoting survival, proliferation and chemoresistance of the leukaemic clone: inhibiting the signals that orchestrate these events is key to disrupting both disease maintenance and progression, thus offering a potential cure for CLL.
Our findings that PKCα subversion can act as an oncogenic trigger in B cells, have prompted us to develop an in vivo pre-clinical model to test potential novel therapeutic agents. This has been developed in parallel with the development of in vitro experimental systems that mimic the in vivo survival- and proliferating-promoting signals present in CLL patient lymphoid organs. Together these translational models can be used for pre-clinical studies to test the efficacy of novel drugs, with the aim of providing improved treatments for CLL that can elicit a cure.
- Identify the molecular events that contribute towards CLL chemo-resistance in the lymphoid organ microenvironment;
- Define the molecular events leading to leukaemogenesis, that are triggered upon inhibition of PKCa signalling;
- Utilise controllable and reproducible CLL models for testing potential novel drugs alone or in combinations in future translational studies.