Identification of CD84 as a potent survival factor in acute myeloid leukemia
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
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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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 7

Knockdown of CD84 triggers mitochondrial stress in AML cells.

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Knockdown of CD84 triggers mitochondrial stress in AML cells. (A) Repres...
(A) Representative transmission electron microscopy images of mitochondrial cristae in HEL cells transfected with shCtrl or shCD84 lentivirus. Scale bars: 1 μm (top); 0.5 μm (bottom). The analysis was conducted in at least 2 independent experimental sets. (B) Western blot of indicated proteins was performed in HEL cells transduced with lentivirus expressing either shCtrl or shCD84, indicating mitochondrial dysfunction in CD84 knockdown cells. Data are representative of 2 independent biological replicates. (C) Interleaved scatter plot showing the MMPs that were measured using JC-1 dye for flow cytometry. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed by 2-tailed unpaired t test. (D) Representative flow cytometry profiles of JC-1–stained THP1, which was transduced with lentiviruses expressing indicated vectors (shCD84 targeting 3′-UTR). Red (PE) and green (FITC) represent the monomers to aggregated ratio. (E) Interleaved scatter plot summarizing the alteration of MMPs shown in D. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed by 1-way ANOVA. (F) Western blot of indicated proteins was performed in THP1 cells transduced with lentivirus expressing either shCtrl, shCD84 (3′-UTR), or shCD84 (3′-UTR) plus CD84-WT. Data are representative of at least 2 independent biological replicates.