伊马替尼在治疗慢性髓细胞白血病(CML)方面非常有效，但初始和获得的伊马替尼耐药性仍然是一大障碍。在BCR-ABL激酶区突变之外，CML耐酪氨酸激酶抑制剂的分子机制仍需要进一步研究。在这里，我们展示了硫氧还蛋白交互蛋白（TXNIP）是一种新颖的BCR-ABL靶基因。TXNIP的抑制是负责BCR-ABL触发的葡萄糖代谢重编程和线粒体稳态的原因。在机制上，Miz-1 / P300复合体通过识别TXNIP核心启动子区域，对TXNIP进行转录激活，并对由伊马替尼或BCR-ABL拟除的c-Myc进行响应。TXNIP的恢复增加了CML细胞对伊马替尼治疗的敏感性，并妨碍了伊马替尼耐药性CML细胞的存活，主要通过阻断糖酵解和葡萄糖氧化，导致线粒体功能障碍和ATP生产。特别是，TXNIP通过Fbw7依赖的c-Myc降解抑制了关键的糖酵解酶，如己糖激酶2（HK2）和乳酸脱氢酶A（LDHA）的表达。相应地，BCR-ABL抑制TXNIP为小鼠骨髓细胞转化提供了一种新的生存途径。TXNIP的敲除加速了BCR-ABL转化，而TXNIP的过表达抑制了这种转化。诱导TXNIP表达的药物与伊马替尼的联合治疗对于患者的CML细胞具有协同杀灭作用，并进一步延长了CML小鼠的生存期。因此，激活TXNIP代表了一种有效的CML治疗策略，可克服耐药性。 ©2023。作者

Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that thioredoxin-interacting protein (TXNIP) is a novel BCR-ABL target gene. Suppression of TXNIP was responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provided a novel survival pathway for the transformation of mouse bone marrow cells. Knockout of TXNIP accelerated BCR-ABL transformation, whereas TXNIP overexpression suppressed this transformation. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.© 2023. The Author(s).