ArticleScience translational medicine2025
Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.
Article in Science translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia.Leukemia · 2026Article
- Natural extract-derived compounds for the treatment of hematological diseases through modulation of the bone marrow microenvironment.Frontiers in chemistry · 2026Review
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Authors and funding
22 authors.
Funding
Abstract
Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, as a critical regulator of MYC expression and BET inhibitor sensitivity in human acute myeloid leukemia (AML). Constitutive or pharmacological activation of AHR repressed MYC and synergized with BET inhibitors to inhibit MYC transcription and suppress leukemia growth across diverse AML models. Mechanistically, AHR directly up-regulated a noncanonical target, ELMSAN1, a component of the MiDAC histone deacetylase complex, which promotes histone deacetylation at MYC regulatory elements. ELMSAN1 depletion led to up-regulation of MYC and impaired AHR signaling-induced BET inhibitor sensitization. In vivo, AHR agonists enhanced BET inhibitor efficacy in patient-derived xenografts and murine leukemia models, enabling the use of lower BET inhibitor doses while preserving therapeutic benefit and reducing toxicity. This combination suppressed leukemia stem cell (LSC) gene signatures and reduced LSC frequency, with minimal impact on normal hematopoietic stem and progenitor cells in both human cord blood xenografts and immunocompetent mouse models. Together, these findings uncover a MYC-repressive, nongenetic AHR-ELMSAN1 axis that enhances BET-targeting therapies and selectively impairs LSCs, providing a compelling rationale for clinical translation in AML and potentially other MYC-driven cancers.
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