PhD student in functional epigenomics

Multiple Myeloma (MM) is an incurable disease with an extremely poor 10-year survival rate (~29%). It is caused by uncontrolled proliferation of the plasma cells. Over the last decade there have been several advances in its treatment, such as immunomodulators and proteasome inhibitors, however it remains incurable.

Unfortunately, therapy resistance remains a major challenge, as resistant cells eventually regrow, causing relapse. Cancer cells evade programmed cell death through the activity of anti-apoptotic BCL-2 family proteins. An imbalance in this complex interplay of the BCL-2 family can result in unrestricted cell proliferation. Due to its anti- apoptotic function, many cancers become dependent on BCL-2 to evade cell death. In particular, MM patients harbouring the t(11;14) translocation have a strong dependence on BCL-2. This process of is one of the classic hallmarks of cancer which makes the anti-apoptotic BCL-2 family proteins attractive therapeutic targets.

This project will define the mechanism-of-action of differential dependency of MM on BCL-2. Specifically, examining epigenetic regulation of BCL-2 expression and resistance to BCL-2 inhibition. Using a combination of in vitro and primary patient samples, this project will epigenetically map BCL-2 regulation, and use functional genomics screens to identify sensitizing mutations to BCL-2 inhibitor therapy. This will primarily involve wet-lab experimentation using functional genomics assays (4C-seq, CRISPR, CUT&RUN/CUT&Tag). This inter-disciplinary project will involve close collaboration with clinical haematologists at Beaumont hospital, wet-lab & computational biologists and international research groups.