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

Ying‐Hui ZhuDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAMariam MurtadhaDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAMiaomiao LiuState Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, ChinaEnrico CasertaDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAOttavio NapolitanoDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USALe Xuan Truong NguyenDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAHuafeng WangDepartment of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, ChinaMilad MoloudizargariDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USALokesh NigamDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USATheophilus TandohDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAXuemei WangState Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, ChinaAlexander PozhitkovDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USARui SuDepartment of Systems Biology, Beckman Research Institute,Xiangjie LinDepartment of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, ChinaMarc Denisse EstepaDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USARaju PillaiDepartment of Pathology, andJoo Y. SongDepartment of Pathology, andJames F. SanchezJudy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, andYu-Hsuan FuDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USALianjun ZhangDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAMan LiDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USABin ZhangDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USALing LiDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAYa-Huei KuoDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USASteven T. RosenJudy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, andGuido MarcucciDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USAJohn C. WilliamsDepartment of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, USAFlavia PichiorriDepartment of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, California, USA

2025en

ABI

Annotatsiya

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.

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DOI: 10.1172/jci176818

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