Understanding and Targeting Aberrant Splicing and NMD in MDS
EvansMDS Young Investigator Award
Nonsense-mediated mRNA Decay (NMD) is a surveillance mechanism that selectively degrades erroneous transcripts with a premature termination codon (PTC). Tumor cells often exploit NMD for survival benefit by altering the expression or function of tumor-suppressors, tumorspecific neo-antigens, NMD factors, or RNA-binding proteins. Alterations in NMD are elicited in cancer by NMD-inducing genetic mutations, somatic mutations in NMD factors, or via alternative splicing (such as inclusion of a poison exon, intron retention, etc.). Oncogenic mutations in the splicing factors SRSF2, SF3B1, and U2AF1 constitute ~60% of myelodysplastic syndome (MDS) patients.
My recent work has revealed that MDS-associated mutations in SRSF2 enhance pathogenic NMD induction by promoting deposition of the exon junction complex (EJC) in mRNA linked to aberrant splicing. I uncovered a novel mechanism in MDS in which tumor cells downregulate the expression of key hematopoietic regulators by leveraging alternative splicing-coupled NMD (AS-NMD) via somatic mutations in SRSF2. Although therapeutic approaches to modulate AS/NMD in several human genetic diseases are reaching the clinic, this is an unexplored area in MDS. Here I will determine whether mutations in SF3B1 and U2AF1 play specific biochemical roles in NMD and whether targeting AS-NMD using directed antisense oligonucleotides (ASO) could be a potential therapeutic strategy for spliceosomal-mutant MDS.