{Reference Type}: Journal Article
{Title}: Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.
{Author}: Huang CY;Chung YH;Wu SY;Wang HY;Lin CY;Yang TJ;Fang JM;Hu CM;Chang ZF;
{Journal}: Commun Biol
{Volume}: 7
{Issue}: 1
{Year}: 2024 Jul 10
{Factor}: 6.548
{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.