The KDM-family inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing a ferroptosis-like phenotype.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with various molecular and cytogenetic subtypes. Treatment options for older adult patients are limited due to high toxicity of conventional chemotherapy. The B-cell leukemia/lymphoma 2 inhibitor venetoclax is effective in combination with hypomethylating agents or low-dose cytarabine, but ∼30% of patients do not respond to the initial combination treatment. Thus, alternative combinations are needed to sensitize AML cells to venetoclax and overcome resistance mechanisms. Here, we report that targeting histone lysine-specific demethylases induces a ferroptosis-like phenotype driven by oxidative stress in various AML subtypes. In both patient samples and cell lines, JIB-04 increases the level of reactive oxygen species, ferrous iron, and lipid peroxidation, all signs of ferroptosis. The combination of JIB-04 and venetoclax proved to be highly synergistic. Blocking the JIB-04-induced phenotype by using the antioxidant N-acetyl-l-cysteine reverses the synergistic killing. At the molecular level, the ferroptosis inducers HMOX1, SAT1, and PTGS2 were found to be upregulated by JIB-04. Collectively, these findings identify JIB-04 as a potential new ferroptosis inducer in AML and highlight the potential of oxidative stress induction as a valuable strategy in combination with venetoclax to treat AML.