Search

This thesis examines the roles of two crucial gene expression regulators- collectively called “Mediator kinases”- in the normal and malignant intestines. It identifies new functions of these genes in maintaining intestinal homeostasis and establishes that these genes function as tumour suppressors in the pre-malignant stage of colorectal cancer.

The JAK2V617F mutation triggers constitutive activation of the JAK2 signalling pathway via STAT3 and STAT5 to drive expression of genes that govern disease phenotypes in myeloproliferative neoplasms (MPNs). The current JAK2 inhibitors (JAK2i) are effective in alleviating symptoms but do not reduce the JAK2 mutant allele burden and may lead to re-activation of compensatory resistance mechanisms. This thesis sought to identify novel targets by deciphering the transcriptional regulation of the central JAK-STAT signalling pathway in human erythroid and JAK2V617F-positive MPN cell models. The findings will aid in the identification of better biomarkers and targeted therapies for MPNs.