Xinyue Zhou, Steven Moreira, Cecilia Restelli, Hong Wang, Soheil Jahangiri, Sajesan Aryal, Emily Tsao, Pengcheng Zhang, Mingming Niu, Harish Kumar, Zaldy Balde, Ana Vujovic, Lina Liu, Nicholas Wong, Andrea Arruda, Mark D. Minden, Yang Zhou, Bhatia Ravi, Jun Qi, Chunliang Li, Kristin J. Hope, Rui Lu
{"title":"Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models","authors":"Xinyue Zhou, Steven Moreira, Cecilia Restelli, Hong Wang, Soheil Jahangiri, Sajesan Aryal, Emily Tsao, Pengcheng Zhang, Mingming Niu, Harish Kumar, Zaldy Balde, Ana Vujovic, Lina Liu, Nicholas Wong, Andrea Arruda, Mark D. Minden, Yang Zhou, Bhatia Ravi, Jun Qi, Chunliang Li, Kristin J. Hope, Rui Lu","doi":"10.1126/scitranslmed.adn5400","DOIUrl":null,"url":null,"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.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"20 1","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1126/scitranslmed.adn5400","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.