Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitive to diosmetin. Knockdown of ERβ confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERβ with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618–26. ©2017 AACR.

中文翻译：

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雌激素受体β是急性髓系白血病的新靶点

急性髓性白血病 (AML) 是一种破坏性疾病，其特征是患者预后不佳和化疗药物不理想。在这里，高通量筛选鉴定了具有抗 AML 活性的柑橘类黄酮diosmetin。Diosmetin 在体外和体内对白血病和白血病干细胞具有选择性毒性，对正常造血干细胞没有影响。从机制上讲，我们证明了地奥司他汀靶向雌激素受体 (ER) β。ERβ 表达赋予细胞敏感性，因为具有高水平 ERβ 的患者来源的 AML 细胞是敏感的，而具有低 ERβ 的细胞对地奥司美丁不敏感。ERβ 的敲低证实了耐药性，而过表达增强了对地奥司汀的敏感性，这被证明是由活性氧信号介导的。总之，这些研究强调了用地奥司美丁靶向 ERβ 作为治疗 AML 的潜在新治疗策略。摩尔癌症治疗; 16(11); 2618-26。©2017 AACR。