Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK

  • Commun Biol. 2024 Jul 10;7(1):843. doi: 10.1038/s42003-024-06547-1.
Chang-Yu Huang  1 ,  Yin-Hsuan Chung  1 ,  Sheng-Yang Wu  1 ,  Hsin-Yen Wang  1 ,  Chih-Yu Lin  2 ,  Tsung-Jung Yang  3 ,  Jim-Min Fang  3 ,  Chun-Mei Hu  4 ,  Zee-Fen Chang  5  6
Affiliations
  • 1. Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
  • 3. Institute of Chemistry, National Taiwan University, Taipei, Taiwan.
  • 4. Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • 5. Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
  • 6. Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
PMID: 38987326 DOI: 10.1038/s42003-024-06547-1
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.

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