biostudies-literatureEagle KNCRR NIH HHSNIDDK NIH HHSNCI NIH HHS386-399.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC8903199biostudies-literatureUnknown29(3)Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models, we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other seleCell stem cellAn oncogenic enhancer encodes selective selenium dependency in AML.PMC8903199R01 CA215452T32 DK060445R01 CA193235S10 RR024574R01 CA255813P30 CA125123Jiang YHu TKoren JVPerez MWEagle KShi XLi MObholzer NPKitano ANakada DYi JSLin CYfalseAn oncogenic enhancer encodes selective selenium dependency in AML.Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models, we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other sele2022-01-01T00:00:00Z2022 Mar2026-05-29T01:19:03.21Z2024-11-15T22:18:29.261ZS-EPMC89031993510851910.1016/j.stem.2022.01.003