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Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis

Dieter Tulkens, Marthe Boelens (UGent) , Thomas Naert (UGent) , Marjolein Carron (UGent) , Suzan Demuynck (UGent) , Sylviane Dewaele (UGent) , Gert Van Isterdael (UGent) , David Creytens (UGent) , Tim Pieters (UGent) , Steven Goossens (UGent) , et al.
(2023) LEUKEMIA. 37. p.2404-2413
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Abstract
CRISPR-mediated simultaneous targeting of candidate tumor suppressor genes in Xenopus tropicalis allows fast functional assessment of co-driver genes for various solid tumors. Genotyping of tumors that emerge in the mosaic mutant animals rapidly exposes the gene mutations under positive selection for tumor establishment. However, applying this simple approach to the blood lineage has not been attempted. Multiple hematologic malignancies have mutations in EZH2, encoding the catalytic subunit of the Polycomb Repressive Complex 2. Interestingly, EZH2 can act as an oncogene or a tumor suppressor, depending on cellular context and disease stage. We show here that mosaic CRISPR/Cas9 mediated ezh2 disruption in the blood lineage resulted in early and penetrant acute myeloid leukemia (AML) induction. While animals were co-targeted with an sgRNA that induces notch1 gain-of-function mutations, sequencing of leukemias revealed positive selection towards biallelic ezh2 mutations regardless of notch1 mutational status. Co-targeting dnm2, recurrently mutated in T/ETP-ALL, induced a switch from myeloid towards acute T-cell leukemia. Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.
Keywords
Oncology, Cancer Research, Hematology

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Citation

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MLA
Tulkens, Dieter, et al. “Mutations in the Histone Methyltransferase Ezh2 Drive Context-Dependent Leukemia in Xenopus Tropicalis.” LEUKEMIA, vol. 37, Springer Science and Business Media LLC, 2023, pp. 2404–13, doi:10.1038/s41375-023-02052-2.
APA
Tulkens, D., Boelens, M., Naert, T., Carron, M., Demuynck, S., Dewaele, S., … Vleminckx, K. (2023). Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis. LEUKEMIA, 37, 2404–2413. https://doi.org/10.1038/s41375-023-02052-2
Chicago author-date
Tulkens, Dieter, Marthe Boelens, Thomas Naert, Marjolein Carron, Suzan Demuynck, Sylviane Dewaele, Gert Van Isterdael, et al. 2023. “Mutations in the Histone Methyltransferase Ezh2 Drive Context-Dependent Leukemia in Xenopus Tropicalis.” LEUKEMIA 37: 2404–13. https://doi.org/10.1038/s41375-023-02052-2.
Chicago author-date (all authors)
Tulkens, Dieter, Marthe Boelens, Thomas Naert, Marjolein Carron, Suzan Demuynck, Sylviane Dewaele, Gert Van Isterdael, David Creytens, Tim Pieters, Steven Goossens, Pieter Van Vlierberghe, and Kris Vleminckx. 2023. “Mutations in the Histone Methyltransferase Ezh2 Drive Context-Dependent Leukemia in Xenopus Tropicalis.” LEUKEMIA 37: 2404–2413. doi:10.1038/s41375-023-02052-2.
Vancouver
1.
Tulkens D, Boelens M, Naert T, Carron M, Demuynck S, Dewaele S, et al. Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis. LEUKEMIA. 2023;37:2404–13.
IEEE
[1]
D. Tulkens et al., “Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis,” LEUKEMIA, vol. 37, pp. 2404–2413, 2023.
@article{01HE2PBBEC72SFCS49B1RYTS5H,
  abstract     = {{CRISPR-mediated simultaneous targeting of candidate tumor suppressor genes in Xenopus tropicalis allows fast functional assessment of co-driver genes for various solid tumors. Genotyping of tumors that emerge in the mosaic mutant animals rapidly exposes the gene mutations under positive selection for tumor establishment. However, applying this simple approach to the blood lineage has not been attempted. Multiple hematologic malignancies have mutations in EZH2, encoding the catalytic subunit of the Polycomb Repressive Complex 2. Interestingly, EZH2 can act as an oncogene or a tumor suppressor, depending on cellular context and disease stage. We show here that mosaic CRISPR/Cas9 mediated ezh2 disruption in the blood lineage resulted in early and penetrant acute myeloid leukemia (AML) induction. While animals were co-targeted with an sgRNA that induces notch1 gain-of-function mutations, sequencing of leukemias revealed positive selection towards biallelic ezh2 mutations regardless of notch1 mutational status. Co-targeting dnm2, recurrently mutated in T/ETP-ALL, induced a switch from myeloid towards acute T-cell leukemia. Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.}},
  author       = {{Tulkens, Dieter and Boelens, Marthe and Naert, Thomas and Carron, Marjolein and Demuynck, Suzan and Dewaele, Sylviane and Van Isterdael, Gert and Creytens, David and Pieters, Tim and Goossens, Steven and Van Vlierberghe, Pieter and Vleminckx, Kris}},
  issn         = {{0887-6924}},
  journal      = {{LEUKEMIA}},
  keywords     = {{Oncology,Cancer Research,Hematology}},
  language     = {{eng}},
  pages        = {{2404--2413}},
  publisher    = {{Springer Science and Business Media LLC}},
  title        = {{Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis}},
  url          = {{http://doi.org/10.1038/s41375-023-02052-2}},
  volume       = {{37}},
  year         = {{2023}},
}
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