G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells
Athena Kyrkou1,2, Robert Valla1,2, Yao Zhang1,2
1German Cancer Research Center (DKFZ), Division B140, 69120, Heidelberg, Germany.
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.
Insights
Researchers identified synthetic-lethal genes targeting Neurofibromatosis Type II (NFII). Inhibiting Glucose-6-phosphate dehydrogenase (G6PD) shows promise for treating NFII by targeting cancer cells.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Neurofibromatosis Type II (NFII) is a genetic disorder caused by NF2 gene mutations.
- NFII leads to tumors like Schwann cell tumors, meningiomas, and ependymomas.
- Limited pharmacological treatments exist for NFII.
Purpose of the Study:
- To identify synthetic-lethal genes that selectively kill NF2-mutant cells.
- To find potential therapeutic targets for Neurofibromatosis Type II.
Main Methods:
- Genome-wide CRISPR/Cas9 screening was employed.
- NF2 mutant and wildtype Schwann cells were compared.
- Gene expression and cellular redox states were analyzed.
Main Results:
- ACSL3 and G6PD were identified as synthetic-lethal partners of NF2.
- NF2-mutant cells exhibit increased oxidative stress.
- Reduced expression of NADPH-generating genes, like ME1, contributes to oxidative stress.
Conclusions:
- Dual inhibition of NADPH-generating pathways (like G6PD and ME1) is lethal to NF2-mutant cells.
- Glucose-6-phosphate dehydrogenase (G6PD) is a potential therapeutic target for NFII due to its role in NADPH generation and its genetic tolerability in humans.
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