Top

Mohammad A. Rahman, Ph.D.
Understanding and Targeting Aberrant Splicing and NMD in MDS

Mohammad A. Rahman, Ph.D.

Cold Spring Harbor Laboratory

2020 Funding recipient

Understanding and Targeting Aberrant Splicing and NMD in MDS

EvansMDS Young Investigator Award

PROJECT SUMMARY

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.