ResultsOur study shows that TP53 mutations in AML cells lead to...

Results

Our study shows that TP53 mutations in AML cells lead to increased resistance to CAR T-cells in vitro. CAR T-cells co-incubated with target TP53-mutant AML blasts exhibited decreased proliferation and increased exhaustion compared to wild-type TP53 AML blasts. Live-cell imaging revealed longer time-to-killing of TP53-mutant than wild-type TP53AML cells upon attack by CAR T-cells, which ultimately led to an inability of CAR T-cells to control TP53-mutant cells. Furthermore, immunodeficient mice xenografted with TP53-mutant AML and treated with CAR T-cells exhibit shorter survival compared to mice engrafted with wild-type TP53AML. Transcriptional profiling of AML cells with either wild-type or mutant TP53 under CAR T-cell attack revealed upregulation of the mevalonate synthesis pathway in TP53-mutant AML cells. Simultaneously, CAR T-cells engaging TP53-mutant AML demonstrated a downregulated Wnt pathway. Rational pharmacological targeting of either of these pathways rescued TP53-mutant AML cell sensitivity to CAR T-cell-mediated killing. Similarly, CRISPR/Cas9-engineering of CAR T-cells to upregulate Wnt pathway signaling rescued TP53-mutant AML cell sensitivity and led to ihttps://www.embopress.org/doi/full/10.1038/s44321-024-00024-2mproved killing efficacy.

Full text: We know already that Bisantrene has an effect on TP53:

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