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.
View: Text | PDF
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

×

Figure 2

CD84 deletion dampens AML survival in both AML cell lines and cell-derived xenograft.

Options: View larger image (or click on image) Download as PowerPoint
CD84 deletion dampens AML survival in both AML cell lines and cell-deriv...
(A) Western blot of the indicated proteins in THP1 cells and HEL cells transduced with 2 shRNAs against CD84 (shCD84-1; shCD84-2) or scramble control (shCtrl). Data are representative of at least 2 independent experiments. (B) Cell proliferative analysis of THP1 cells and HEL cells transduced with shCtrl or shCD84 lentiviral vectors. (C) Bar chart showing apoptosis levels indicated by annexin-APC/DAPI in 3 AML patient specimens transduced with shCtrl or shCD84 lentiviral vector. (D and E) AML cells obtained from 3 different donors (AML #1, #3, #8) were transduced with shCtrl or shCD84 lentivirus. Representative colony images are in D. The graph in E shows AML colony-formation cell (CFC) frequencies after 10 days of culture. n = 3 independent replicates per sample. (F) Bioluminescent imaging showing the tumor burden in xenograft NSG mice on days 14–35 following shCtrl- or shCD84-transduced THP1-luciferase cell transplantation (n = 5 per group). (G) Kaplan-Meier analysis of survival of THP1-luciferase cell–transplanted (shCtrl or shCD84) NSG mice. Each group consisted of 5 mice. (H) Bioluminescent imaging showing the tumor burden in xenograft NSG mice on days 19–41 following mock/shCtrl-, CD84-OE/shCtrl–, or CD84-OE/shCD84–transduced THP1-luciferase cell transplantation (n = 4 per group). (I) Kaplan-Meier analysis of survival of THP1-luciferase cell–transplanted (mock/shCtrl, CD84-OE/shCtrl, or CD84-OE/shCD84) NSG mice (n = 4 per group). (J) Bar chart showing the CD84 surface expression in BM cells from NSG mice xenografted with THP1 luciferase cells transduced with mock/shCtrl or CD84-OE/shCD84. Data are represented as mean ± SEM and are representative of 3 biological replicates (B and E) and 3 independent experiments (C). Each dot in J represents 1 mouse. Statistical significance was assessed by 2-way ANOVA (B, D, and E); 2-way ANOVA (mix model; C); log-rank test (G and I); and 2-tailed unpaired t test (J).