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CRISPR-Cas9 screen reveals that inhibition of enhancer of zeste homolog 2 sensitizes malignant T cells to dimethyl-fumarate-induced cell death

Constitutive activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a hallmark of many lymphocyte-associated cancers, including cutaneous T-cell lymphoma (CTCL) and its leukemic variant, the Sézary syndrome. Dimethyl fumarate (DMF) has been identified as...

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Main Authors: Teubner, Jan P. (Author) , Tümen, Deniz (Author) , Kandulski, Arne (Author) , Heumann, Philipp (Author) , Mester, Patricia (Author) , Aschenbrenner, Elisabeth (Author) , Pollinger, Kirstin (Author) , Gunckel, Manuela (Author) , Volz, Barbara (Author) , Hein, Tobias (Author) , Beltzig, Paul L. (Author) , Tengler, Luisa (Author) , Voll, Florian (Author) , Kreutz, Marina (Author) , Kunst, Claudia (Author) , Nicolay, Jan Peter (Author) , Müller-Schilling, Martina (Author) , Gülow, Karsten (Author)
Format: Article (Journal)
Language:English
Published: 2025
In: The FEBS journal
Year: 2025, Pages: 1-17
ISSN:1742-4658
DOI:10.1111/febs.70208
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1111/febs.70208
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/febs.70208
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Author Notes:Jan P. Teubner, Deniz Tümen, Arne Kandulski, Philipp Heumann, Patricia Mester, Elisabeth Aschenbrenner, Kirstin Pollinger, Manuela Gunckel, Barbara Volz, Tobias Hein, Paul L. Beltzig, Luisa Tengler, Florian Voll, Marina Kreutz, Claudia Kunst, Jan P. Nicolay, Martina Müller and Karsten Gülow

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520 |a Constitutive activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a hallmark of many lymphocyte-associated cancers, including cutaneous T-cell lymphoma (CTCL) and its leukemic variant, the Sézary syndrome. Dimethyl fumarate (DMF) has been identified as a promising NF-κB-targeted therapy and has shown positive outcomes in a phase II clinical trial involving patients with Sézary syndrome. However, limited responsiveness remains a significant challenge. Through a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen, we identified enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase) as a critical target for enhancing DMF-induced cell death. EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is responsible for the methylation of histone H3 (H3K27). Combining DMF with the US Food and Drug Administration (FDA)-approved EZH2 inhibitor tazemetostat significantly increases cell death in patient-derived CTCL cells, offering a promising strategy to improve therapeutic outcomes and overcome limited responsiveness to DMF. 
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