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 5

CD84 is essential for AML maintenance in inv(16) mouse model.

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CD84 is essential for AML maintenance in inv(16) mouse model. (A) Histog...
(A) Histogram and violin chart showing CD84 expression in inv(16) c-kit+ cells relative to WT c-kit+ cells. Data are represented as mean ± SEM and are representative of 3 independent experiments and mice. Statistical significance was assessed by 2-tailed unpaired t test. (B) Connecting line graph representing cell proliferative analysis of inv(16)-AML cells transduced with shCtrl or shCD84 (shCD84-1; shCD84-2) lentiviral vector. Data are represented as mean ± SEM and are representative of 3 independent experiments. Statistical significance was assessed with 2-way ANOVA (mixed model). (C) Violin plot showing apoptosis levels indicated by annexin-APC/DAPI in inv(16)-AML cells transduced with shCtrl or shCD84 lentiviral vector. Data are represented as mean ± SEM and are representative of 4 independent experiments. Statistical significance was assessed by 1-way ANOVA. (D) Representative flow cytometry profile of donor cells (mouse CD45.2) engrafted in BM from shCtrl-inv(16) or shCD84-inv(16) transplanted mice. (E) Scatter plot showing the leukemic engraftment in the BM of recipient mice (CD45.1) xenografted with inv(16) AML with or without CD84 silencing (CD45.2) (n = 5 per group). Data are represented as mean ± SEM and are representative of 5 individual mice. Statistical significance was assessed by 2-tailed unpaired t test. (F) Representative colony images of inv(16)-AML cells transduced with shCtrl or shCD84-1+2. Original magnificiation, 10×. (G) The bar graph shows colony formation numbers of inv(16) mice transduced with shCtrl or shCD84-1+2 after 7 days of culture. Data are represented as mean ± SEM and are representative of 7 independent replicates. Statistical significance was assessed by 2-tailed unpaired t test.