Identification of CD84 as a potent survival factor in acute myeloid leukemia.
Publication Year:
2025
PubMed ID:
40198133
Public Summary:
CD84: A Newly Discovered Lifeline for Leukemia Cells—and a Potential Weak Spot
Acute myeloid leukemia (AML) is an aggressive blood cancer that often resists treatment and has poor survival rates, especially in older patients. Our research uncovered a key player in this disease: a protein called CD84. We found that AML cells rely heavily on CD84 to stay alive and grow. When CD84 levels are high, leukemia cells thrive; when CD84 is reduced, these cells struggle to survive and cannot spread effectively.
Why is CD84 so important? It helps leukemia cells manage energy and protect themselves from harmful molecules called reactive oxygen species (ROS), which can damage cells. CD84 does this by supporting the cell’s power plants—mitochondria—and boosting antioxidant defenses through a pathway involving a protein called NRF2. Without CD84, leukemia cells lose this protection, their energy systems fail, and they die.
Our experiments in human cells, patient samples, and mouse models all point to the same conclusion: CD84 is a critical survival factor for AML. This discovery opens the door to new treatments that target CD84, potentially making leukemia cells more vulnerable and improving outcomes for patients.
Scientific 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.
