Identification of CD84 as a potent survival factor in acute myeloid leukemia
Yinghui Zhu, … , John C. Williams, Flavia Pichiorri
Yinghui Zhu, … , John C. Williams, Flavia Pichiorri
Published April 8, 2025
Citation Information: J Clin Invest. 2025;135(11):e176818. https://doi.org/10.1172/JCI176818.
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Research Article Cell biology Hematology Oncology

Identification of CD84 as a potent survival factor in acute myeloid leukemia

Abstract

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.

Authors

Yinghui Zhu, Mariam Murtadha, Miaomiao Liu, Enrico Caserta, Ottavio Napolitano, Le Xuan Truong Nguyen, Huafeng Wang, Milad Moloudizargari, Lokesh Nigam, Theophilus Tandoh, Xuemei Wang, Alex Pozhitkov, Rui Su, Xiangjie Lin, Marc Denisse Estepa, Raju Pillai, Joo Song, James F. Sanchez, Yu-Hsuan Fu, Lianjun Zhang, Man Li, Bin Zhang, Ling Li, Ya-Huei Kuo, Steven Rosen, Guido Marcucci, John C. Williams, Flavia Pichiorri

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Figure 8

CD84 knockdown impairs GSH metabolism and NRF2 antioxidant defense, leading to mitochondrial dysfunction in AML.

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CD84 knockdown impairs GSH metabolism and NRF2 antioxidant defense, lead...
(A) Bar chart showing the KEGG pathway enrichment analysis of differentially expressed core genes in both THP1 cells and HEL cells. (B) Heatmap visualization of NRF2-regulated antioxidant and detoxification enzyme expression according to our RNA-Seq dataset. (C) The violin plot showing the mRNA expression of key antioxidant/detoxification genes in THP1 cells and HEL cells transduced with shCtrl or shCD84. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed by 2-tailed unpaired t test. (D) Immunoblot detection of indicated proteins involved in GSH biosynthesis in THP1 cells and HEL cells transduced with shCtrl or shCD84 for 72 hours. Data are representative of at least 2 independent biological replicates. (E and F) Representative histogram (E) and violin chart (F) showing the effects of CD84 knockdown on intracellular ROS generation in THP1 cells and HEL cells transduced with shCtrl or shCD84 for 72 hours. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed by 2-tailed unpaired t test. (G) The violin plot shows the intracellular GSH levels in THP1 cells and HEL cells that were transduced with shCtrl or shCD84 for 72 hours. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed by 2-tailed unpaired t test. (H) Immunoblot analysis of the expression of NRF2 in the cytoplasm and nucleus of HEL and THP1 cells stably expressing CD84 shRNA (targeting 3’UTR). Data are representative of at least 2 independent experiments. (I) Representative confocal microscopy images and violin chart showing the nucleoplasm distribution of NRF2 in THP1 cells transduced with either shCtrl or shCD84 lentivirus. The intensity of nuclear fluorescence was quantified in the violin plot. Data are represented as mean ± SEM and are representative of 4 independent images. Statistical significance was assessed by 2-tailed unpaired t test.