Journal
CELL STEM CELL
Volume 29, Issue 3, Pages 386-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2022.01.003
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Funding
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- NIH [R01CA215452, R01CA193235, R01CA 255813, T32DK060445, P30 CA125123, S10 RR024574]
- CPRIT [RR150093, RP160283]
- NIH
- NCI [R01CA21545S]
- CPRIT Core Facility Support Award [CPRIT-RP180672]
- NIH K12 Clinical Pharmacology Faculty Fellowship
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Transcription deregulation is a characteristic of AML, driving oncogenic expression. Through enhancer mapping, AML-specific enhancers were found to encode for more selective tumor dependencies. A MYB-regulated enhancer in AML was found to regulate SEPHS2, a key component of the selenoprotein production pathway. This enhancer upregulates SEPHS2, promoting selenoprotein production and AML survival.
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 selenoprotein pathway genes are required for AML growth in vitro. SEPHS2 knockout and selenium dietary restriction significantly delay leukemogenesis in vivo with little effect on normal hematopoiesis. These data validate the utility of enhancer mapping in target identification and suggest that selenoprotein production is an actionable target in AML.
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