Histidine re-sensitizes pediatric acute lymphoblastic leukemia to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
14 Mar 2024
14 Mar 2024
Historique:
received:
31
08
2023
accepted:
07
03
2024
revised:
05
03
2024
medline:
18
3
2024
pubmed:
15
3
2024
entrez:
15
3
2024
Statut:
epublish
Résumé
Despite progressive improvements in the survival rate of pediatric B-cell lineage acute lymphoblastic leukemia (B-ALL), chemoresistance-induced disease progression and recurrence still occur with poor prognosis, thus highlighting the urgent need to eradicate drug resistance in B-ALL. The 6-mercaptopurine (6-MP) is the backbone of ALL combination chemotherapy, and resistance to it is crucially related to relapse. The present study couples chemoresistance in pediatric B-ALL with histidine metabolism deficiency. Evidence was provided that histidine supplementation significantly shifts the 6-MP dose-response in 6-MP-resistant B-ALL. It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.
Identifiants
pubmed: 38485947
doi: 10.1038/s41419-024-06599-5
pii: 10.1038/s41419-024-06599-5
pmc: PMC10940622
doi:
Substances chimiques
Mercaptopurine
E7WED276I5
Histidine
4QD397987E
SIRT5 protein, human
EC 3.5.1.-
Sirtuins
EC 3.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
216Informations de copyright
© 2024. The Author(s).
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