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AML PATIENTS WITH WILDTYPE TP53 AND DEFECTIVE TP53-MEDIATED APOPTOSIS HAVE A DISMAL SURVIVAL

ABSTRACT: The survival of 10% of patients with acute myelogenous leukemia (AML) carrying mutations in TP53 is dismal. Here, we estimated the fraction of AML patients with impaired TP53-mediated apoptosis despite TP53 WT status and their survival. We report the results of a detailed characterization of responses to treatment with the MDM2 inhibitor MI219, a p53 protein stabilizer, ex vivo in AML blasts from 165 patients. In total 33% of AML were resistant to MDM2 inhibitor induced apoptosis, of which 15% carried TP53 mutation and 18% were TP53 WT. We conducted array-based expression profiling of ten resistant and ten sensitive AML cases all with WT TP53, respectively, at baseline and after 2h and 6h of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 responses genes, this was largely absent in resistant cases. The sensitive and resistant AML samples at baseline furthermore differed in the expression of inflammation-related and mitochondrial genes. Clinically, the survival of TP53 mutated AML or AML with defective MDM2 inhibitor induced TP53-mediated apoptosis despite WT TP53 in this cohort was 0% and 11%, respectively. In summary, we show prevalent multi-causal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297461 | GEO | 2026/01/07

REPOSITORIES: GEO

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