https://orcid.org/0000-0002-0162-1162
Key Points
PPARγ up-regulation upon VEN/DEC-induced PPARG promoter hypomethylation resulted in FAO activation and treatment resistance.
Pharmacological inhibition of PPARγ enhanced sensitivity to VEN/DEC in resistant AML, suggesting PPARγ as a potential therapeutic target.
ABSTRACT
The combination of the BCL2 inhibitor venetoclax and the hypomethylating agent decitabine (VEN/DEC) constitutes a primary therapeutic strategy for treating older adults with acute myeloid leukemia (AML). However, a notable subset of patients exhibits resistance to VEN/DEC, demonstrating either no disease response or relapse after initial remission. This study aimed to elucidate the molecular mechanisms underlying this resistance through analyses of gene expression and DNA methylation profiles. We conducted comprehensive RNA sequencing analysis and DNA methylation profiling on AML samples from 35 patients undergoing VEN/DEC therapy. The RNA sequencing analysis revealed that several genes related to fatty acid metabolism were significantly upregulated in leukemia cells from patients who received VEN/DEC treatment and relapsed or failed to respond. Increased expression of peroxisome proliferator-activated receptor gamma (PPARG) occurred after treatment and correlated with decitabine-induced promoter hypomethylation. Subsequent in vitro validation demonstrated that decitabine treatment results in hypomethylation of the PPARG promoter, elevating PPARG levels and promoting a metabolic environment characterized by enhanced fatty acid oxidation pathways conducive to VEN/DEC resistance. Furthermore, pharmacological inhibition using either a PPARγ antagonist or a fatty acid oxidation inhibitor enhanced the sensitivity of resistant cells to VEN/DEC, underscoring the crucial role of PPARγ in the development of therapeutic resistance. These findings not only shed light on the metabolic adaptation that contributes to VEN/DEC resistance in AML but also identify PPARγ as a potential therapeutic target for overcoming such resistance, providing new opportunities to improve the efficacy of VEN/DEC-based therapy in AML.
