Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models

IF 14.6 1区 医学 Q1 CELL BIOLOGY
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
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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.
在临床前模型中,非遗传性AHR-ELMSAN1轴的激活优化了bet靶向治疗并抑制了白血病干细胞
开发增强对溴结构域和外结构域(BET)抑制剂的反应并有效根除癌症干细胞的策略将代表针对白血病的主要癌症治疗进展。通过功能性CRISPR筛选,我们确定了芳烃受体(AHR),一种配体激活的转录因子,是人类急性髓性白血病(AML)中MYC表达和BET抑制剂敏感性的关键调节因子。AHR的组成性或药理学激活抑制MYC,并与BET抑制剂协同抑制MYC转录并抑制各种AML模型的白血病生长。在机制上,AHR直接上调了一个非规范靶标ELMSAN1,它是MiDAC组蛋白去乙酰化酶复合物的一个组成部分,促进MYC调节元件的组蛋白去乙酰化。ELMSAN1缺失导致MYC上调和AHR信号诱导的BET抑制剂致敏性受损。在体内,AHR激动剂在患者来源的异种移植物和小鼠白血病模型中增强了BET抑制剂的功效,使使用较低的BET抑制剂剂量同时保持治疗效果并降低毒性。这种组合抑制了白血病干细胞(LSC)的基因特征并降低了LSC的频率,对人类脐带血异种移植和免疫能力小鼠模型中的正常造血干细胞和祖细胞的影响最小。总之,这些发现揭示了myc抑制,非遗传性AHR-ELMSAN1轴,增强了bet靶向治疗并选择性损害LSCs,为AML和潜在的其他myc驱动的癌症的临床转化提供了令人信服的理由。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
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.
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