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Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.
- Source :
-
Communications biology [Commun Biol] 2024 Jul 10; Vol. 7 (1), pp. 843. Date of Electronic Publication: 2024 Jul 10. - Publication Year :
- 2024
-
Abstract
- Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Mice
Protein Kinase Inhibitors pharmacology
Drug Resistance, Neoplasm drug effects
Cell Line, Tumor
Fusion Proteins, bcr-abl metabolism
Fusion Proteins, bcr-abl genetics
Fusion Proteins, bcr-abl antagonists & inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
Glutathione metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 38987326
- Full Text :
- https://doi.org/10.1038/s42003-024-06547-1