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

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 provide survival advantage to leukemia cells, whereas CD84 downregulation disrupts their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocks leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulates leukemia cells’ energy metabolism and mitochondrial dynamics. Depletion of CD84 alters mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2) impairing AML antioxidant defense. Conversely, CD84 over-expression stabilizes NRF2 and promotes 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 pro-survival pathways, highlighting a previously unexplored therapeutic vulnerability of leukemia cells.