Zhou Xinyue, Moreira Steven, Restelli Cecilia, Wang Hong, Jahangiri Soheil, Aryal Sajesan, Tsao Emily, Zhang Pengcheng, Niu Mingming, Kumar Harish, Balde Zaldy, Vujovic Ana, Liu Lina, Wong Nicholas, Arruda Andrea, Minden Mark D, Zhou Yang, Ravi Bhatia, Qi Jun, Li Chunliang, Hope Kristin J, Lu Rui
Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA.
O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA.
Sci Transl Med. 2025 Aug 6;17(810):eadn5400. doi: 10.1126/scitranslmed.adn5400.
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.
制定增强对溴结构域和额外末端结构域（BET）抑制剂的反应并有效根除癌症干细胞的策略，将代表白血病癌症治疗的一项重大进展。通过功能性CRISPR筛选，我们确定芳烃受体（AHR），一种配体激活的转录因子，是人类急性髓系白血病（AML）中MYC表达和BET抑制剂敏感性的关键调节因子。AHR的组成型或药理学激活抑制MYC，并与BET抑制剂协同作用，以抑制MYC转录并在多种AML模型中抑制白血病生长。从机制上讲，AHR直接上调一个非经典靶点ELMSAN1，它是MiDAC组蛋白脱乙酰酶复合物的一个组成部分，可促进MYC调控元件处的组蛋白脱乙酰化。ELMSAN1的缺失导致MYC上调，并削弱AHR信号诱导的BET抑制剂致敏作用。在体内，AHR激动剂增强了BET抑制剂在患者来源的异种移植模型和小鼠白血病模型中的疗效，使得可以使用更低剂量的BET抑制剂，同时保留治疗益处并降低毒性。这种联合抑制了白血病干细胞（LSC）基因特征并降低了LSC频率，对人脐血异种移植模型和免疫健全小鼠模型中的正常造血干细胞和祖细胞影响最小。总之，这些发现揭示了一个抑制MYC的、非基因的AHR-ELMSAN1轴，该轴增强了靶向BET的疗法并选择性损害LSC，为AML及可能其他MYC驱动癌症的临床转化提供了令人信服的理论依据。
