在TP53突变型急性髓系白血病中诱导铜死亡

Patients with acute myeloid leukemia (AML) carrying TP53 loss-of-function mutations exhibit extremely poor outcomes, partly due to intrinsic resistance to current treatments such as intensive chemotherapy and venetoclax-based regimens that depend on p53-mediated apoptosis. Developing therapeutic strategies capable of bypassing defective apoptotic pathways and eliminating TP53 -deficient AML remains a critical need. Copper ionophores, including elesclomol-a compound previously evaluated in clinical trials-and its next-generation analog UM4118, trigger a mitochondria-dependent, nonapoptotic mode of copper-regulated cell death known as cuproptosis. Here, we demonstrate that inducing cuproptosis through these agents effectively targets AML cells in a p53-independent manner.Analysis of the BEAT AML 2.0 dataset revealed that the copper ionophore elesclomol exhibits the strongest anti-leukemic activity in TP53 -mutated AML cells compared with TP53 wild-type counterparts. Based on this observation, we hypothesized that cuproptosis induction could suppress AML cell growth and survival independent of p53 status. To test this, TP53 was disrupted via CRISPR-Cas9 gene editing in 3 TP53 wild-type human AML cell lines (MOLM13, MV4-11, and UKE-1) to generate isogenic TP53 knockout derivatives, along with UKE-1 clones harboring heterozygous and homozygous TP53 R273H mutations. Short-term viability and growth assays demonstrated a marked, dose-dependent reduction in viability 72 hours after treatment with copper ionophores, with comparable sensitivity across TP53 wild-type, TP53 -KO, and TP53 -deficient (TF-1 and F36P) AML cells. In contrast, cytarabine, idarubicin, and venetoclax activity was substantially diminished in TP53 -deficient cells, consistent with the known resistance of TP53 -mutated AML to these standard therapies. Notably, combining low-dose elesclomol with the hypomethylating agent decitabine, which has established clinical efficacy in TP53-mutated AML, produced a synergistic increase in apoptosis in TP53 -deficient AML cells.Together, these findings demonstrate that copper ionophores can bypass TP53 -associated resistance to AML cell death by activating cuproptosis rather than relying on p53-dependent apoptotic pathways. The robust activity of copper ionophores across diverse TP53 -deficient AML models, coupled with the enhanced efficacy observed in combination with decitabine, underscores cuproptosis induction as a promising therapeutic approach for TP53 -deficient AML.