Communications Biology (Jul 2024)

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

  • Chang-Yu Huang,
  • Yin-Hsuan Chung,
  • Sheng-Yang Wu,
  • Hsin-Yen Wang,
  • Chih-Yu Lin,
  • Tsung-Jung Yang,
  • Jim-Min Fang,
  • Chun-Mei Hu,
  • Zee-Fen Chang

DOI
https://doi.org/10.1038/s42003-024-06547-1
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

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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.