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 3

CD84 loss impairs AML development in PDX.

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CD84 loss impairs AML development in PDX. (A) Schematic of the design an...
(A) Schematic of the design and procedures of generating a CD84 knockdown, AML PDX model. AML primary patient cells were transduced with shCtrl or shCD84 lentivirus. After puromycin selection, shCtrl or shCD84 AML primary cells were injected into irradiated NSG mice. (B) Representative flow cytometry profile of human AML cells (human CD45+/CD33+) engrafted in BM. (C–E) Scatter plots showing the percentage of human AML cells (human CD45+/CD33+) engrafted in BM (C), SP (D), and PB (E) of recipient NSG mice (n = 5 per group). Data are represented as mean ± SEM and are representative of 5 individual mice per group. Statistical significance was assessed by 2-tailed unpaired t test. (F) Bioluminescent imaging showing the tumor burden in xenograft NSG mice (frontal and dorsal) following shCtrl- or shCD84-transduced AML PDX-luciferase cell transplantation (n = 4 per group). (G) Kaplan-Meier survival analysis of AML PDX-luciferase cell–transplanted (shCtrl or shCD84) NSG mice (n = 4 per group). Statistical significance was assessed by log-rank test. (H) Flow cytometry profile showing apoptosis levels indicated by annexin-APC/DAPI in 32D cells transfected with lentivirus including CD823-mock vector or CD823-CD84 WT. (I) Violin plot showing apoptosis levels indicated by annexin V-APC/DAPI in 32D cells transduced with mock or CD84 WT. Data are represented as mean ± SEM and are representative of 3 biological replicates. Statistical significance was assessed by 2-tailed unpaired t test.