Acute Myeloid Leukemia: a key role of DGKα and DGKζ in cell viability.

Acute myeloid leukemia (AML) is a heterogeneous disease presenting a relevant unmeet clinical need for new therapeutic drugs. We and others reported increased expression of various diacylglycerol kinases (DGK) in AML. Inhere we study the effect of ritanserin, a DGKα specific inhibitor and DGKζ-IN4 / BAY 2965501, DGKζ specific inhibitors, on a panel of AML cell models. We also compared the effects observed with isoform specific silencing and finally explored the effect of those drugs on THP-1 cell proteome. We report that inhibitor sensitivity deeply varies among cell models, and it is not related to the level of target DGK isoform expression. Similarly, some cell lines are sensitive to DGKα silencing (HEL), some to DGKζ silencing (HL-60), while some are resistant to both (THP-1 and K562). Mechanistically, ritanserin deeply affects THP-1 proteome downregulating a significant fraction of proteins, while BAY 2965501 affects a reduced and distinct protein set, indicating distinct mechanisms of action. Those results suggest that targeting AML by DGK isoform specific inhibitors is possible but will require suitable markers for patient stratification.