# Patients with AML with WT TP53 but defective TP53-mediated apoptosis have a dismal survival

## TL;DR

This study shows that some AML patients with normal TP53 genes still have poor survival due to defects in TP53-mediated apoptosis.

## Contribution

The paper identifies a new group of AML patients with WT TP53 but defective apoptosis, showing they have very poor survival.

## Key findings

- 33% of AML patients were resistant to MDM2 inhibitor-induced apoptosis, with 55% of these having WT TP53.
- Resistant AML cases showed no induction of TP53 response genes and had altered inflammation and mitochondrial gene expression.
- AML patients with defective TP53-mediated apoptosis had 4-year survival rates of 19% or 6%, depending on NPM1 status.

## Abstract

The survival of patients with acute myelogenous leukemia (AML) carrying mutations in TP53 is dismal. We report the results of a detailed characterization of responses to treatment ex vivo with the MDM2 inhibitor MI219, a p53 protein stabilizer, in AML blasts from 165 patients focusing analyses on patients with WT TP53. In total 33% of AML were absolute resistant to MDM2 inhibitor–induced apoptosis, of which 45% carried TP53 mutation and 55% were TP53 WT. We conducted array-based expression profiling of 10 resistant and ten sensitive AML cases with WT TP53 status, respectively, at baseline and after 2 hours and 6 hours of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 response genes, this was absent or attenuated in resistant cases. In addition, the sensitive and resistant AML samples at baseline profoundly differed in the expression of inflammation-related and mitochondrial genes. No patient with TP53 mutated AML survived. The 4-year survival of AML with defective MDM2 inhibitor–induced TP53-mediated apoptosis despite WT TP53 was dismal, at 19% when NPM1 was comutated and 6% when NPM1 was WT. In summary, we identified prevalent multicausal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.

In this paper we quantitatively define the AML patients with WT TP53 but defective TP53-mediated apoptosis and show that this group has a dismal long-term survival.