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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Author

Listed:
  • Athena Kyrkou

    (German Cancer Research Center (DKFZ), Division B140
    Institute of Human Genetics)

  • Robert Valla

    (German Cancer Research Center (DKFZ), Division B140
    Institute of Human Genetics)

  • Yao Zhang

    (German Cancer Research Center (DKFZ), Division B140
    Institute of Human Genetics)

  • Giulia Ambrosi

    (Div. Signaling and Functional Genomics)

  • Stephanie Laier

    (German Cancer Research Center (DKFZ))

  • Karin Müller-Decker

    (German Cancer Research Center (DKFZ))

  • Michael Boutros

    (Institute of Human Genetics
    Div. Signaling and Functional Genomics)

  • Aurelio A. Teleman

    (German Cancer Research Center (DKFZ), Division B140
    Institute of Human Genetics)

Abstract

Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.

Suggested Citation

  • Athena Kyrkou & Robert Valla & Yao Zhang & Giulia Ambrosi & Stephanie Laier & Karin Müller-Decker & Michael Boutros & Aurelio A. Teleman, 2024. "G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49298-7
    DOI: 10.1038/s41467-024-49298-7
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    References listed on IDEAS

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    1. Jiao Wu & Alexander M. Minikes & Minghui Gao & Huijie Bian & Yong Li & Brent R. Stockwell & Zhi-Nan Chen & Xuejun Jiang, 2019. "Publisher Correction: Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling," Nature, Nature, vol. 572(7770), pages 20-20, August.
    2. Jiao Wu & Alexander M. Minikes & Minghui Gao & Huijie Bian & Yong Li & Brent R. Stockwell & Zhi-Nan Chen & Xuejun Jiang, 2019. "Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling," Nature, Nature, vol. 572(7769), pages 402-406, August.
    3. Katharina Clemm von Hohenberg & Sandra Müller & Sibylle Schleich & Matthias Meister & Jonathan Bohlen & Thomas G. Hofmann & Aurelio A. Teleman, 2022. "Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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