Serglycin-ROS axis mediates synergistic lethality of PI3Kγ inhibition and Azacitidine in TP53-mutated AML

PURPOSE: To investigate novel combination strategies for TP53-mutated acute myeloid leukemia (AML), focusing on the potential synergy between PI3Kγ inhibition and Azacitidine, and to elucidate the underlying molecular mechanisms. MATERIALS AND METHODS: We detected the expression of PI3Kγ (PIK3CG/PIK3R5) in TP53 mutant and wildtype AML cell lines using the CCLE database, RT-qPCR, and western blot. We evaluated the influence of Azacitidine (AZA) and PI3Kγ inhibitor (Eganelisib) in AML cells, conducted in vivo combination therapy experiments, and identified synergistic targets through RNA sequencing and siRNA technology. RESULTS: TP53-mutated AML showed hypermethylation of PI3Kγ promoters and reduced PI3Kγ expression. AZA treatment selectively activated the PI3Kγ signaling in TP53-mutated cells. Eganelisib combined with AZA demonstrated potent synergy, suppressing proliferation and inducing apoptosis in TP53-mutated AML (ZIP synergy score > 10). This combination extended survival in xenograft models (33.0 vs. 18.0 days, p < 0.01). RNA-seq identified serglycin (SRGN) as a candidate mediator potentially linking AZA-induced transcriptional reprogramming to ROS-mediated cell death. SRGN knockdown elevated ROS levels and sensitized cells to AZA. The combinatorial treatment significantly increased ROS levels compared to monotherapy. CONCLUSION: We provide the first preclinical evidence that PI3Kγ inhibition sensitizes TP53-mutated AML to AZA through a mechanism potentially involving the SRGN-ROS axis, offering a translatable combinatorial strategy for patients with this aggressive leukemia subtype.