UNBIASED FUNCTIONAL VALIDATION OF ALTERNATIVE-SPLICED ISOFORMS IN CANCER

Abstract

Alternative splicing (AS) is a key cellular process, enhancing protein diversity and function, with up to 90% of genes undergoing AS. It has been shown that different isoforms of the same gene can have antagonistic effects. This feature is particularly interesting in malignancy, as some isoforms can be oncogenic, while others may act as tumour suppressors. Inducing the switch from an oncogenic to a tumour suppressive isoform is a feasible, but yet underexplored, therapeutic approach to tackling cancer. Here, we developed a computational pipeline to facilitate splicing analysis in the context of Acute Myeloid Leukemia (AML) and Prostate Cancer (PCa). Upon targeting selected events using AONs, we noticed a preferential depletion of the malignant cells rather than healthy ones. Thus, this thesis offers not only a novel computational method to improve diagnostic power, but also a potential targeted therapy for cancer.