Epigenetics and Cancer: Determining how Mistakes in V(D)J Recombination Trigger Leukaemias and Lymphomas

V(D)J recombination is essential to produce an effective adaptive immune system but since the reaction involves the breakage and rejoining of DNA, it is highly dangerous and errors have long been thought to lead to leukaemias and lymphomas. Recently, we uncovered a novel aberrant recombination reaction, named "cut-and-run" where the recombination by-product, in complex with the recombinase, triggers a series of double strand breaks throughout the genome. Crucially, these breaks correspond to some of those found in patients with Acute Lymphoblastic Leukaemia (ALL), suggesting that cut-and-run could play an important role in the development of ALL. This project aims to further investigate the cut-and-run reaction and whether it truly plays a role in the development of ALL with the longer term aim of developing novel cut-and-run inhibitors.

The four specific objectives are to:

1) Determine if the genomic breakpoints identified in ALL cells are bona fide recombinase targets.

2) Determine if the recombination by-product is present in ALL patient samples and test how long the by-product persists in these cells.

3) Test if the recombination by-product can really lead to disease progression using a model system based on ALL-progenitor cells.

4) Begin analysis of the recombination by-product/recombinase complex for longer term structural studies.

These studies will thus investigate a new mechanism by which a very frequent group of cancers is caused. In the longer term, it is hoped that these studies can help in the understanding of the risk factors, as well as the development of inhibitors, of these devastating diseases.

These studies will provide training in a broad range of modern techniques, including molecular biology, biochemistry, bioinformatics and preliminary structural biology analyses.