Zhu Yinghui, Murtadha Mariam, Liu Miaomiao, Caserta Enrico, Napolitano Ottavio, Nguyen Le Xuan Truong, Wang Huafeng, Moloudizargari Milad, Nigam Lokesh, Tandoh Theophilus, Wang Xuemei, Pozhitkov Alex, Su Rui, Lin Xiangjie, Estepa Marc Denisse, Pillai Raju, Song Joo, Sanchez James F, Fu Yu-Hsuan, Zhang Lianjun, Li Man, Zhang Bin, Li Ling, Kuo Ya-Huei, Rosen Steven, Marcucci Guido, Williams John C, Pichiorri Flavia
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, China.
Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, and.
J Clin Invest. 2025 Apr 8;135(11). doi: 10.1172/JCI176818. eCollection 2025 Jun 2.
Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provided a survival advantage to leukemia cells, whereas CD84 downregulation disrupted their proliferation, clonogenicity, and engraftment capabilities in both human cell lines and patient-derived xenograft cells. Critically, loss of CD84 also markedly blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as a survival factor across species. Mechanistically, CD84 regulated leukemia cells' energy metabolism and mitochondrial dynamics. Depletion of CD84 altered mitochondrial ultrastructure and function of leukemia cells, and it caused downmodulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and downmodulation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing AML antioxidant defense. Conversely, CD84 overexpression stabilized NRF2 and promoted its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicate that AML cells depend on CD84 to support antioxidant prosurvival pathways, highlighting a therapeutic vulnerability of leukemia cells.
急性髓系白血病（AML）是一种侵袭性且往往致命的恶性肿瘤，与增殖性未成熟髓系母细胞相关。在此，我们确定CD84是AML中的关键生存调节因子。高水平的CD84表达为白血病细胞提供了生存优势，而CD84的下调则破坏了它们在人细胞系和患者来源的异种移植细胞中的增殖、克隆形成和植入能力。至关重要的是，CD84的缺失也显著阻断了MLL-AF9和inv(16) AML小鼠模型中的白血病植入和克隆形成，突显了其作为跨物种生存因子的关键作用。从机制上讲，CD84调节白血病细胞的能量代谢和线粒体动力学。CD84的缺失改变了白血病细胞的线粒体超微结构和功能，并导致氧化磷酸化和脂肪酸氧化途径的下调。CD84敲低诱导Akt磷酸化受阻和核因子红细胞2相关因子2（NRF2）的下调，损害AML的抗氧化防御。相反，CD84过表达稳定了NRF2并促进其转录激活，从而支持AML中的氧化还原稳态和线粒体功能。总的来说，我们的研究结果表明AML细胞依赖CD84来支持抗氧化促生存途径，突显了白血病细胞的治疗脆弱性。
