Journal Article

DKFZ-2024-01287

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.

Kyrkou, A. (First author)DKFZ* ; Valla, R.DKFZ* ; Zhang, Y.DKFZ* ; Ambrosi, G.DKFZ* ; Laier, S.DKFZ* ; Müller-Decker, K.DKFZ* ; Boutros, M.DKFZ* ; Teleman, A. (Last author)DKFZ*

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-49298-7

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.

Keyword(s): Schwann Cells: metabolism (MeSH) ; Humans (MeSH) ; CRISPR-Cas Systems (MeSH) ; Glucosephosphate Dehydrogenase: metabolism (MeSH) ; Glucosephosphate Dehydrogenase: genetics (MeSH) ; Neurofibromin 2: metabolism (MeSH) ; Neurofibromin 2: genetics (MeSH) ; Coenzyme A Ligases: metabolism (MeSH) ; Coenzyme A Ligases: genetics (MeSH) ; Synthetic Lethal Mutations (MeSH) ; Animals (MeSH) ; Neurofibromatosis 2: metabolism (MeSH) ; Neurofibromatosis 2: genetics (MeSH) ; NADP: metabolism (MeSH) ; Mice (MeSH) ; Oxidation-Reduction (MeSH) ; Glucosephosphate Dehydrogenase ; Neurofibromin 2 ; Coenzyme A Ligases ; long-chain-fatty-acid-CoA ligase ; G6PD protein, human ; NADP ; NF2 protein, human

Note: #EA:B140#LA:B140#

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Contributing Institute(s):

1. B140 Signal Transduction in Cancer (B140)
2. B110 Signalwege funktionelle Genomik (B110)
3. Gruppe Müller-Decker (W420)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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