TY  - JOUR
AU  - Kyrkou, Athena
AU  - Valla, Robert
AU  - Zhang, Yao
AU  - Ambrosi, Giulia
AU  - Laier, Stephanie
AU  - Müller-Decker, Karin
AU  - Boutros, Michael
AU  - Teleman, Aurelio
TI  - G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-01287
SP  - 5115
PY  - 2024
N1  - #EA:B140#LA:B140#
AB  - 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.
KW  - Schwann Cells: metabolism
KW  - Humans
KW  - CRISPR-Cas Systems
KW  - Glucosephosphate Dehydrogenase: metabolism
KW  - Glucosephosphate Dehydrogenase: genetics
KW  - Neurofibromin 2: metabolism
KW  - Neurofibromin 2: genetics
KW  - Coenzyme A Ligases: metabolism
KW  - Coenzyme A Ligases: genetics
KW  - Synthetic Lethal Mutations
KW  - Animals
KW  - Neurofibromatosis 2: metabolism
KW  - Neurofibromatosis 2: genetics
KW  - NADP: metabolism
KW  - Mice
KW  - Oxidation-Reduction
KW  - Glucosephosphate Dehydrogenase (NLM Chemicals)
KW  - Neurofibromin 2 (NLM Chemicals)
KW  - Coenzyme A Ligases (NLM Chemicals)
KW  - long-chain-fatty-acid-CoA ligase (NLM Chemicals)
KW  - G6PD protein, human (NLM Chemicals)
KW  - NADP (NLM Chemicals)
KW  - NF2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38879607
C2  - pmc:PMC11180199
DO  - DOI:10.1038/s41467-024-49298-7
UR  - https://inrepo02.dkfz.de/record/291067
ER  -