# ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia

## TL;DR

A subgroup of AML patients with high ΔNp73 levels has poor outcomes similar to TP53-mutant AML and may benefit from targeting CEBPA.

## Contribution

Identifies ΔNp73 as a marker for a poor-risk AML subgroup and shows CEBPA regulates its expression.

## Key findings

- High ΔNp73 expression in AML is linked to poor outcomes like TP53-mutant cases.
- ΔNp73 disrupts TP53 signaling by competing for gene targets.
- Inhibiting CEBPA reduces ΔNp73 and restores drug sensitivity in AML cells.

## Abstract

Among acute myeloid leukemia (AML) patients, a subgroup remains notoriously refractory to current treatment options, with underlying mechanisms poorly understood. Here, using a multi-omics approach, we reveal that this resistant patient subgroup is characterized by high expression of the oncogenic TP73 isoform ΔNp73, exhibiting similarly poor outcomes as TP53-mutant AML. ΔNp73, which lacks a transcriptional activation domain but retains chromatin-binding properties, competes with TP53 for specific gene targets, thereby downregulating TP53 signaling. We demonstrate that the transcription factor CEBPA controls ΔNp73 expression in AML cells by binding to an intragenic enhancer region. Genetic or pharmacological inhibition of the transcriptional activity of CEBPA with guanfacine reduces ΔNp73 levels and restores drug sensitivity involving ferroptosis-mediated cell death, acting synergistically with venetoclax. Our study sheds light on a previously undercharacterized poor-risk subgroup of AML, which may support patient stratification and inform treatment considerations.

•A subset of TP53wt patients displays similarities with TP53mut patients with poor prognosis•This subset expresses high levels of ΔNp73, which lacks a transcriptional activation domain•ΔNp73 retains chromatin-binding properties and interferes with TP53 signaling•ΔNp73 expression is controlled by CEBPA via binding to an intragenic enhancer

A subset of TP53wt patients displays similarities with TP53mut patients with poor prognosis

This subset expresses high levels of ΔNp73, which lacks a transcriptional activation domain

ΔNp73 retains chromatin-binding properties and interferes with TP53 signaling

ΔNp73 expression is controlled by CEBPA via binding to an intragenic enhancer

Pereira-Martins et al. identify an AML subgroup with poor prognosis marked by elevated ΔNp73, an oncogenic TP73 isoform. This isoform lacks a transcriptional activation domain and competes with TP53 for specific targets. ΔNp73 expression is regulated by CEBPA via binding to an intragenic enhancer, which is amendable to pharmacological targeting.