An antisense antidote to oncogenic poison exons

Area of Science:

• Molecular biology
• Cancer genetics
• RNA splicing

Background:

• Splicing factors, like SRSF2, are often mutated in myeloid cancers.
• These mutations lead to aberrant RNA splicing, affecting tumor suppressor gene expression.
• In SRSF2-mutated cancers, a specific oncogenic event involves the inclusion of a poison exon in EZH2 mRNA.

Purpose of the Study:

• To elucidate the mechanism by which mutant SRSF2 binding leads to poison exon inclusion in EZH2.
• To identify therapeutic strategies targeting this oncogenic splicing event.
• To evaluate the potential of antisense oligonucleotides in restoring EZH2 function.

Main Methods:

• Investigated the binding of mutant SRSF2 to the poison exon.
• Utilized antisense oligonucleotides to target and repress the poison exon.
• Assessed the restoration of EZH2 function and rescue of hematopoietic defects.

Main Results:

• Defined the mechanism of mutant SRSF2-mediated poison exon inclusion.
• Identified an antisense oligonucleotide that effectively represses the poison exon.
• Demonstrated that this repression restores EZH2 function and rescues hematopoietic defects in preclinical models.

Conclusions:

• Mutant SRSF2 binding to poison exons is a key oncogenic event in myeloid cancers.
• Targeting poison exons with antisense oligonucleotides is a promising therapeutic strategy.
• Restoring EZH2 function via poison exon repression offers a novel approach to cancer treatment.