CRISPR-mediated correction of oncogenic AS-NMD in splicing factor mutant cancer
- 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
- 2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences
- 3Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences
Abstract
Alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD) evolved as a master regulator of gene expression. Dysregulated AS-NMD has been identified as the root of many human maladies, from developmental defects to deadly cancer. Poison exons (PEs) are highly conserved alternative exons that contain a premature termination codon and elicit AS-NMD when included in a transcript. Cancer cells often exploit the inclusion of PEs to downregulate tumor suppressors or the exclusion of PEs to upregulate oncoproteins. Therefore, PEs have drawn significant attention as a novel therapeutic avenue for cancer and other diseases. It was previously reported that an oncogenic mutation in the splicing factor SRSF2 promotes downregulation of the tumor suppressor EZH2 by including a PE, resulting in altered chromatin regulation, defective hematopoiesis, and cancer development. Here, we examine a therapeutic proof-of-concept for manipulating PE-mediated oncogenic AS-NMD using a CRISPR-based approach. Using paired guide RNA, we successfully deleted the PE of EZH2 from the genome of SRSF2-mutated leukemia. This editing resulted in EZH2 mRNAs without a PE, and restored EZH2 protein expression. This subsequently restored Polycomb Repressive Complex 2 (PRC2) association, and global H3K27 histone methylation. The proposed CRISPR strategy provides compelling evidence for correcting oncogenic PE inclusion, highlighting its potential for therapeutic application against PE in cancer and other human diseases.
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BibTeX
@article{nagar2026crisprmediated,
title = {{CRISPR-mediated correction of oncogenic AS-NMD in splicing factor mutant cancer}},
author = {Preeti Nagar and Md Rafikul Islam and Nirjhor Anuvob Rahman and Shabiha Afroj Heeamoni and Md Mahbub Hasan and Saaimatul Huq and Fariha Alam Bushra and Mengye Hu and Rezwan Ali and Mokarram Hossain and Mohammad Alinoor Rahman},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1958532},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1958532/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CRISPR-mediated correction of oncogenic AS-NMD in splicing factor mutant cancer
AU - Preeti Nagar
AU - Md Rafikul Islam
AU - Nirjhor Anuvob Rahman
AU - Shabiha Afroj Heeamoni
AU - Md Mahbub Hasan
AU - Saaimatul Huq
AU - Fariha Alam Bushra
AU - Mengye Hu
AU - Rezwan Ali
AU - Mokarram Hossain
AU - Mohammad Alinoor Rahman
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1958532
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1958532/full
AB - Alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD) evolved as a master regulator of gene expression. Dysregulated AS-NMD has been identified as the root of many human maladies, from developmental defects to deadly cancer. Poison exons (PEs) are highly conserved alternative exons that contain a premature termination codon and elicit AS-NMD when included in a transcript. Cancer cells often exploit the inclusion of PEs to downregulate tumor suppressors or the exclusion of PEs to upregulate oncoproteins. Therefore, PEs have drawn significant attention as a novel therapeutic avenue for cancer and other diseases. It was previously reported that an oncogenic mutation in the splicing factor SRSF2 promotes downregulation of the tumor suppressor EZH2 by including a PE, resulting in altered chromatin regulation, defective hematopoiesis, and cancer development. Here, we examine a therapeutic proof-of-concept for manipulating PE-mediated oncogenic AS-NMD using a CRISPR-based approach. Using paired guide RNA, we successfully deleted the PE of EZH2 from the genome of SRSF2-mutated leukemia. This editing resulted in EZH2 mRNAs without a PE, and restored EZH2 protein expression. This subsequently restored Polycomb Repressive Complex 2 (PRC2) association, and global H3K27 histone methylation. The proposed CRISPR strategy provides compelling evidence for correcting oncogenic PE inclusion, highlighting its potential for therapeutic application against PE in cancer and other human diseases.
SN - 1664-3224
ER -