Acute Myeloid Leukemia: A Key Role of DGKα and DGKζ in Cell Viability.

Acute myeloid leukemia (AML) is a heterogeneous disease with an unmet need for novel therapeutic drugs. Previous studies have reported the upregulation of diacylglycerol kinases (DGKs) in AML. This study investigated the effects of ritanserin, a DGKα-specific inhibitor, and DGKζ-IN4 or BAY 2965501, DGKζ-selective inhibitors, on a panel of AML cell lines. Ritanserin induced apoptotic cell death across all tested models, whereas DGKζ inhibitors triggered both apoptosis and necrosis to variable extents, with HL-60 cells being the most responsive to both compounds. Drug sensitivity did not correlate with DGKα or DGKζ expression levels, indicating that additional factors may influence cellular susceptibility. THP-1 proteomic profiling revealed that ritanserin broadly downregulated proteins involved in antigen presentation, cell cycle and metabolism, while BAY 2965501 affected a smaller and distinct but functionally similar protein subset, implying different mechanisms of action. Gene silencing confirmed AML cell line-specific dependence on DGK isoforms: HEL cells were sensitive to DGKα knockdown, HL-60 to DGKζ silencing, whereas K562 and THP-1 were resistant to both. These findings indicate that DGKs targeting can effectively reduce AML cell viability. However, AML heterogeneity and the limited selectivity of current inhibitors underscore the need for predictive biomarkers and combinatorial strategies to translate DGK inhibition into effective therapy.