Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Apoptosis
CRISPR-Cas Systems
Cell Cycle
Cell Proliferation
Drug Resistance, Neoplasm
/ drug effects
Enzyme Inhibitors
/ pharmacology
Female
Folic Acid
/ metabolism
Glycine Hydroxymethyltransferase
/ antagonists & inhibitors
Humans
Methotrexate
/ pharmacology
Mice
Mice, Inbred NOD
Mice, SCID
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Prognosis
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
02
02
2020
accepted:
20
07
2021
revised:
08
07
2021
pubmed:
4
8
2021
medline:
16
2
2022
entrez:
3
8
2021
Statut:
ppublish
Résumé
Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.
Identifiants
pubmed: 34341479
doi: 10.1038/s41375-021-01361-8
pii: 10.1038/s41375-021-01361-8
pmc: PMC8807390
mid: NIHMS1726552
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Enzyme Inhibitors
0
Folic Acid
935E97BOY8
Glycine Hydroxymethyltransferase
EC 2.1.2.1
SHMT protein, human
EC 2.1.2.1
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
348-360Subventions
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : European Research Council
ID : 758848
Pays : International
Organisme : NCI NIH HHS
ID : K08 CA222684
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA236036
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242379
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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