Oncogenic-driven “specialization” of mRNA splicing in hematological cancers

This proposal directly investigates the mechanisms by which oncogenic stress hijacks splicing to derail gene expression in tumor cells. Splicing is a central RNA-based process decoding genetic information commonly deregulated in human cancers. How oncogenic pathways usurp the splicing machinery, spliceosome, to promote tumorigenesis remains largely unresolved.

We recently uncovered a hardwired translation-driven program centered on core splice factors (SFs), SF3B1 and SF3A3, rewiring splicing in MYC hyperactive cancers (Cieśla et al., Mol Cell2021 and 2023). Mechanistically, this involves cis-translation regulatory elements (TREs) such as RNA structures and modifications.

Building on our pioneer work, my group will study how oncogenic-driven SF translation “specializes” the spliceosome to adapt gene expression and direct critical tumorigenic transitions in vivo.

Specifically, we will: (1) harness SF3A3 translation using TRE deficient mice to map single-cell identity during lymphomagenesis; (2) capture splicing “specialization” leveraging multi-omics to define spliceosomal composition and function heterogeneity in lymphoma; (3) chart how perturbed SF translation drives cancer-promoting splicing in human lymphoma and leukemia.

The transformative findings from this project will uncover new post-transcriptional facets of gene expression control in malignant cells, which may serve as a springboard for developing novel therapeutic strategies targeting mRNA splicing in cancer.