?Np73 isoform defines a TP53mutant-like poor risk subgroup of acute myeloid leukemia

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 ?Np73, exhibiting similarly poor outcomes as TP53-mutant AML. ?Np73, 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 ?Np73 expression in AML cells by binding to an intragenic enhancer region. Genetic or pharmacological inhibition of the transcriptional activity of CEBPA with guanfacine reduces ?Np73 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. Overall design: RNA-seq profiling of MOLM13 cell models containing 1) cDNA-DNp73 to overexpress the DNp73 isoform, 2) CRISPR-Cas9 knockout of the intragenic region +24Kb TSS of the TP73 gene and 3) the empty vector/scrambled control.