Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
Commun Biol. 2024 Jul 10;7(1):843. doi: 10.1038/s42003-024-06547-1.
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.
Bcr-Abl 转化导致慢性髓性白血病 (CML)。获得 T315I 突变会导致酪氨酸激酶抑制剂 (TKI) 耐药。本研究开发了一种化合物 JMF4073，抑制胸苷酸 (TMP) 和胞苷酸 (CMP) 激酶，旨在为 TKI 耐药的 CML 提供新的治疗方法。JMF4073 的体外和体内治疗消除了 WT-Bcr-Abl-32D CML 细胞。然而，T315I-Bcr-Abl-32D 细胞对 JMF4073 的敏感性较低。有证据表明，ATF4 介导的 GSH 上调导致 T315I-Bcr-Abl-32D 细胞对 JMF4073 的敏感性降低。减少 GSH 生物合成会在 T315I-Bcr-Abl-32D 细胞中产生复制应激，这些细胞需要 dTTP/dCTP 合成才能存活，从而使 JMF4073 具有敏感性。进一步表明，几种人 CML 急变期细胞系中的 ATF4 和 GSH 水平与 JMF4073 敏感性呈负相关，JMF4073 与 GSH 还原剂联合治疗会导致这些 CML 急变期细胞系的合成致死性。总之，该研究表明了 CML 治疗的另一种选择。
