A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.

摘要: Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development various cancers, including leukemia. Here, we describe antileukemic activity and mechanism action T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis leukemia cell lines revealed that acute erythroid (AEL) megakaryoblastic cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, disrupted interaction between factor-independent 1B (GFI1B), transcription factor critical for differentiation processes megakaryocytic Knockdown GFI1B recapitulated T-3775440-induced suppression, highlighting significance LSD1-GFI1B axis inhibition with regard anti-AML effects T-3775440. Moreover, exhibited significant antitumor efficacy AEL AMKL xenograft models. Our findings provide rationale evaluating inhibitors potential treatments indicate against AML, particularly AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.