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@ARTICLE{Kyrkou:291067,
author = {A. Kyrkou$^*$ and R. Valla$^*$ and Y. Zhang$^*$ and G.
Ambrosi$^*$ and S. Laier$^*$ and K. Müller-Decker$^*$ and
M. Boutros$^*$ and A. Teleman$^*$},
title = {{G}6{PD} and {ACSL}3 are synthetic lethal partners of {NF}2
in {S}chwann cells.},
journal = {Nature Communications},
volume = {15},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DKFZ-2024-01287},
pages = {5115},
year = {2024},
note = {#EA:B140#LA:B140#},
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.},
keywords = {Schwann Cells: metabolism / Humans / CRISPR-Cas Systems /
Glucosephosphate Dehydrogenase: metabolism /
Glucosephosphate Dehydrogenase: genetics / Neurofibromin 2:
metabolism / Neurofibromin 2: genetics / Coenzyme A Ligases:
metabolism / Coenzyme A Ligases: genetics / Synthetic Lethal
Mutations / Animals / Neurofibromatosis 2: metabolism /
Neurofibromatosis 2: genetics / NADP: metabolism / Mice /
Oxidation-Reduction / Glucosephosphate Dehydrogenase (NLM
Chemicals) / Neurofibromin 2 (NLM Chemicals) / Coenzyme A
Ligases (NLM Chemicals) / long-chain-fatty-acid-CoA ligase
(NLM Chemicals) / G6PD protein, human (NLM Chemicals) / NADP
(NLM Chemicals) / NF2 protein, human (NLM Chemicals)},
cin = {B140 / B110 / W420},
ddc = {500},
cid = {I:(DE-He78)B140-20160331 / I:(DE-He78)B110-20160331 /
I:(DE-He78)W420-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38879607},
pmc = {pmc:PMC11180199},
doi = {10.1038/s41467-024-49298-7},
url = {https://inrepo02.dkfz.de/record/291067},
}