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 1

CD84 is overexpressed in AML.

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CD84 is overexpressed in AML. (A) BM cells were subjected to CyTOF immun...
(A) BM cells were subjected to CyTOF immunophenotyping comprising 39 surface markers tailored to detect different immune subsets. Analysis was performed with Cytobank platform in independent healthy donors (n = 3). (B) Scatter plots of CD84 mRNA expression in BM-MNCs from patients with AML (n = 542) and healthy donors (n = 73) (from GEO GSE13159 dataset) indicating increased CD84 expression in AML specimens. Graphs are presented as mean ± SEM. Statistical significance was assessed by 2-tailed unpaired t test. (C) Scatter plots of CD84 mRNA expression in leukemia blasts from patients with AML (n = 26) and CD34+ cells isolated from healthy donors (n = 38) (from GEO GSE9476 dataset) indicating increased CD84 expression in AML specimens. Graphs are presented as mean ± SEM. Statistical significance was assessed by 2-tailed unpaired t test. (D) Histogram showing CD84 surface protein expression in different AML patient specimens (n = 31) as analyzed by flow cytometry, highlighting that CD84 is highly expressed in AML primary patient cells. PE anti-human CD84 (clone CD84.1.21; BioLegend) was used (1 μl/test). (E) Histogram showing flow cytometry profiles of CD84 expression in healthy donors from the CD34+ cellular population. The analysis was conducted in independent donors (n = 5). (F) Violin plot shown the percentage of CD84-expressing cells among AML primary patients (n = 31), AML cell lines (n = 9), and healthy donor cells (n = 5). Data are represented as mean ± SEM. Statistical significance was assessed by 1-way ANOVA. (G) Representative images of immunohistochemical staining of CD84 performed in normal tissue array. Each normal tissue stained for CD84 was obtained from a minimum of 3 independent normal donors. Scale bars: 50 μm. (H) Representative images of immunohistochemical staining of CD84 in AML BM. Original magnification, ×200. Scale bars: 200 μm. The analysis was conducted in 15 independent AML donor biopsies (see also Supplemental Figure 2G).