An oncogenic enhancer encodes selective selenium dependency in AML

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Transcriptional deregulation is a key feature of acute myeloid leukemia (AML), driving cancer-specific expression patterns.
• Identifying unique vulnerabilities in AML is crucial for developing targeted therapies.

Purpose of the Study:

• To identify novel, actionable therapeutic targets in AML by integrating enhancer landscapes with genetic dependency data.
• To investigate the role of a specific MYB-regulated enhancer and its downstream gene, SEPHS2, in AML pathogenesis.

Main Methods:

• Integrated pan-cancer enhancer mapping with genetic dependency profiling.
• Utilized patient-derived samples and mouse models to study gene regulation and function.
• Performed SEPHS2 knockout studies and selenium dietary restriction experiments.

Main Results:

• Discovered an AML-enriched enhancer regulated by MYB, which controls SEPHS2 expression.
• Demonstrated that SEPHS2 upregulation promotes antioxidant function essential for AML cell survival.
• Showed that SEPHS2 and selenoprotein pathway genes are vital for AML growth in vitro and in vivo.
• Found that SEPHS2 inhibition or selenium restriction delays leukemogenesis with minimal impact on normal hematopoiesis.

Conclusions:

• Enhancer mapping is a valuable tool for identifying selective cancer dependencies.
• The selenoprotein production pathway, regulated by SEPHS2, represents a promising therapeutic target for AML.