Estrogen Receptor β Is a Novel Target in Acute Myeloid Leukemia

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) beta. ER beta expression conferred cell sensitivity, as patient-derived AML cells with high levels of ER beta were sensitive, whereas cells with low ERb were insensitive to diosmetin. Knockdown of ER beta 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 ER beta with diosmetin as a potential novel therapeutic strategy for the treatment of AML. (C) 2017 AACR.