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 4

CD84 is essential for AML maintenance in vivo.

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CD84 is essential for AML maintenance in vivo. (A) Design and procedures...
(A) Design and procedures of generating an MLL-AF9 AML mouse model with CD84 knockdown. (B) Violin chart showing CD84 expression in c-kit+ cells before and after MLL-AF9 transduction. (C) Connecting line graph representing cell-proliferative analysis of MLL-AF9 AML cells transduced with shCtrl or shCD84 (shCD84-1; shCD84-2) lentiviral vector. (D) Representative colony formation images of MLL-AF9 c-kit+ cells transduced with shCtrl or shCD84 (shCD84-1; shCD84-2). Images were acquired in tiles by the City of Hope microscopy core facility using ZEN 3.1 (blue edition, Carl Zeiss Microscopy GmbH). Original maginifcation, ×10. (E) The graph shows MLL-AF9 AML colony formation cell numbers after 7 days of culture. (F) Representative scatter plots showing the percentage of donor cells (mouse CD45.2) transduced with shCtrl or shCD84 and engrafted in the BM. (G and H) Graphs showing the percentages of mouse CD45.2 in the BM (G) and SP (H) of recipient mice (mouse CD45.1) at around 5 weeks after BM transplantation (n = 5 per group). (I) Representative SP image of recipient mice xenografted with shCtrl-MLL-AF9 or shCD84-MLL-AF9. (J) Representative images of Wright-Giemsa staining of BM from recipient mice transplanted with shCtrl-MLL-AF9 or shCD84-MLL-AF9 AML cells (red arrows indicate AML blast). (K and L) Representative scatter plot (K) and associated graph (L) showing the leukemic engraftment in the PB of recipient mice (CD45.1) xenografted with MLL-AF9 AML with or without CD84 silencing (CD45.2) upon secondary BM transplantation on day 38. (M) Kaplan-Meier analysis of survival of secondary BM-transplanted mice with MLL-AF9 cells (shCtrl or shCD84) (n = 5 per group). Data are represented as ± SEM and are representative of 3 independent experiments (B, C, and E), 5 individual mice (G and H); and 5 individual mice per group (L). Statistical significance was assessed by 2-tailed unpaired t test (B, G, H, and L); 2-way ANOVA (mixed model; C); 1-way ANOVA (E); and log-rank test (M).