Our project aimed to determine the mechanisms whereby alterations in the structural packaging of DNA and the communication between different DNA sequence elements, potentially over long distances, control gene expression, subsequent protein manufacture and through this, cellular behaviour and the mechanisms whereby these processes are altered and subverted to generate cancer. As an exemplar, we chose the tractable tumour Acute Myeloid Leukaemia (AML), focusing on the subtype with predicted loss-of-function mutation of the Cohesin complex. This complex is a global regulator of interactions between DNA segments over long distances through the looping out of intervening DNA, and by controlling enhancer and promoter interactions, and thought to regulate gene expression. M utations in Cohesin complex members occur frequently in other forms of cancer, suggesting the Cohesin complex alter DNA topology and with it gene expression across multiple cell types. This finding is consistent with the fact that alterations of gene expression are present and drive almost every type of cancer.
Cancer is now the most common cause of death amongst western populations. With our ageing population, deaths from malignant disease are predicted to continue increasing. Even in survivors of cancer, continued morbidity brings a significant burden of patient suffering. Financially, cancer patients are lost to the workforce due to death or an inability to perform their duties and cancer treatments are becoming increasing complicated and expensive. Better knowledge of the causes of cancer and improved therapies are key in detecting or preventing developing cases earlier and in treating established cases better and with lower toxicities.
Our project has been highly successful in meeting all its objectives. We established both a cell line and in vivo system of Cohesin loss/depletion and used these to shed considerable light on the function of Cohesin, in particular during cellular processes that require dynamic gene regulation. We also specifically and mechanistically dissected the role of Cohesin in erythroid differentiation, establishing that Cohesin depletion abrogates induction of dynamic erythroid transcriptional programmes and that Cohesin-dependent dynamic gene expression upon erythroid differentiation is both prespecified and repressed by Etv6 in stem cells. We are currently examining the role of loss of Cohesin function in the maintenance of malignant self-renewal and are determining ways to therapeutically target this. These observations have led us to conclude that Etv6 activity is a potential therapeutic target, to induce differentiation in both AML and MDS, preparing the way for screens to identify an effective compound.
