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

GSE219135 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2024/04/24 Platform GPL11154
Summary
Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently 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 cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.
Published in
G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells
Kyrkou A, Valla R, Zhang Y et al. · Nature communications 2024 · PMID 38879607 · doi:10.1038/s41467-024-49298-7
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Also filed as BioProject PRJNA907235 and SRA study SRP410823. Searching any of these in the dataset finder brings you back here.

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