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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.
摘要：
Bcr-Abl转化导致慢性髓性白血病(CML)。T315I突变的获得导致酪氨酸激酶抑制剂（TKI）耐药。这项研究开发了一种化合物，JMF4073，抑制胸苷酸（TMP）和胞苷酸（CMP）激酶，旨在针对TKI抗性CML的新疗法。JMF4073的体外和体内处理消除了WT-Bcr-Abl-32DCML细胞。然而,T315I-Bcr-Abl-32D细胞不易受到JMF4073的攻击。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，需要dTTP/dCTP合成才能存活，从而使JMF4073敏感性。它进一步表明，ATF4和GSH的水平在几个人CML母细胞危机细胞系与JMF4073的敏感性负相关，JMF4073与GSH还原剂的组合处理导致这些CML爆炸危机线中的合成致死性。总之,本研究显示了CML治疗的替代选择.
