Functional Interpretation of Transcriptome and Translatome Dynamics In Cancer

Abstract

The differential production of transcript isoforms from gene loci is a key cellular mechanism. Yet, its impact on protein production remains an open question. We describe new methodologies developed to address this question in the context of cancer. We present a new computational tool for the translation quantification of individual transcript isoforms using ribosome-protected mRNA fragments. Analysis of samples from glia and glioma uncovered a widespread and evolutionarily conserved impact of differential splicing on translation with potential functional relevance in brain cancer. Furthermore, we describe the analysis of the dynamics of the transcriptome in B-cell acute leukaemia (B-ALL), where a significant proportion of patients still have a dismal prognosis due to yet undetermined mechanisms. We identified an expression signature that is common in patients with fusions associated with poor outcomes. This signature led us to uncover a network of splicing factors potentially controlling the splicing of genes associated with high risk. Our findings provide evidence for a convergent mechanism of aberrant RNA processing that sustains a malignant phenotype in a subset of gene-fusion-driven B-ALL cases.