Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2017 Dec 13;8(1):2099. doi: 10.1038/s41467-017-02290-w.
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
急性髓系白血病（AML）的有效治疗仍然是一个未满足的需求。Ten-eleven translocation 1（TET1）是 AML 中的关键癌蛋白。通过一系列数据分析和药物筛选，我们鉴定出两种化合物（即 NSC-311068 和 NSC-370284），它们选择性地抑制 TET1 转录和 5-羟甲基胞嘧啶（5hmC）修饰，并有效抑制 TET1 高表达的 AML（即 TET1-高 AML）的细胞活力，包括携带 t(11q23)/MLL 重排和 t(8;21)AML 的 AML。NSC-311068 特别是 NSC-370284，在体内显著抑制 TET1-高 AML 的进展。UC-514321 是 NSC-370284 的结构类似物，对 TET1-高 AML 小鼠的治疗效果更强，中位生存期延长了三倍以上。NSC-370284 和 UC-514321 均直接靶向 TET1 的转录激活因子 STAT3/5，从而抑制 TET1 的表达。它们与标准化疗也具有很强的协同作用。我们的研究结果强调了通过选择性抑制剂靶向 STAT/TET1 轴在 AML 治疗中的治疗潜力。
