Targeting EZH2 oncogenic splicing: decoding the regulatory network and antisense correction

Islam, Md Rafikul, Nagar, Preeti, McNaughton, Naomi, Heeamoni, Shabiha Afroj, Hasan, Md Mahbub, Kandel, Shila, Mukta, Israt Jahan, Tsakiroglou, Panagiotis, Dalton, William Brian, Abdel-Wahab, Omar, Krainer, Adrian R, Rahman, Mohammad Alinoor (August 2026) Targeting EZH2 oncogenic splicing: decoding the regulatory network and antisense correction. Genes & Development. ISSN 0890-9369

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Abstract

Recurrent mutations in splicing factors (SFs) have been established as crucial drivers of tumorigenesis in several types of blood cancer and are also common in a variety of solid tumors. Mutations change the RNA-binding preferences of SFs, promote global splicing alterations, and often generate erroneous mRNAs that are then degraded by nonsense-mediated mRNA decay (NMD). Consequently, several critical genes linked to hematopoiesis are dysregulated, leading to blood cancer. Although the field has progressed considerably in identifying aberrant genes and affected pathways, effective therapies have not yet emerged. To address this key gap, we instigated a gene-specific targeted strategy by unlocking the regulatory network. As a proof of concept, we scrutinized a tumor suppressor gene, EZH2, which is a bona fide target in SRSF2 mutated cancer. We precisely defined splicing cis-elements in EZH2 transcripts and illustrated the dynamic choreography of regulatory proteins in the entire splicing and NMD catalytic pathways. We then designed antisense oligonucleotides (ASOs) targeting important regulatory sites. Our lead ASO successfully corrects aberrant splicing and NMD, restores the expression and function of EZH2, and partially rescues hematopoietic defects and cellular properties. Our study demonstrates that ASO pharmacology is an actionable strategy for clinical development, challenging the existing paradigms in SF mutated cancers.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics
CSHL Authors:	Krainer, Adrian R.
Communities:	CSHL labs > Krainer lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 August 2026
Date Deposited:	10 Aug 2026 13:18
Last Modified:	10 Aug 2026 13:18
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42288

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