Guanosine primes acute myeloid leukemia for differentiation via guanine nucleotide salvage synthesis.
Acute myeloid leukemia
HPRT1
PNP
guanosine 5’-triphosphate
myeloid differentiation
Journal
American journal of cancer research
ISSN: 2156-6976
Titre abrégé: Am J Cancer Res
Pays: United States
ID NLM: 101549944
Informations de publication
Date de publication:
2022
2022
Historique:
received:
22
11
2021
accepted:
27
12
2021
entrez:
10
2
2022
pubmed:
11
2
2022
medline:
11
2
2022
Statut:
epublish
Résumé
Differentiation arrest represents a distinct hallmark of acute myeloid leukemia (AML). Identification of differentiation-induction agents that are effective across various subtypes remains an unmet challenge. GTP biosynthesis is elevated in several types of cancers, considered to support uncontrolled tumor growth. Here we report that GTP overload by supplementation of guanosine, the nucleoside precursor of GTP, poises AML cells for differentiation and growth inhibition. Transcriptome profiling of guanosine-treated AML cells reveals a myeloid differentiation pattern. Importantly, the treatment compromises leukemia progression in AML xenograft models. Mechanistically, GTP overproduction requires sequential metabolic conversions executed by the purine salvage biosynthesis pathway including the involvement of purine nucleoside phosphorylase (PNP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1). Taken together, our study offers novel metabolic insights tethering GTP homeostasis to myeloid differentiation and provides an experimental basis for further clinical investigations of guanosine or guanine nucleotides in the treatment of AML patients.
Types de publication
Journal Article
Langues
eng
Pagination
427-444Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Informations de copyright
AJCR Copyright © 2022.
Déclaration de conflit d'intérêts
None.
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