Wild-Type p53 Overexpression in NPM1-Mutated AML: Potential Implications for Disease Biology and Therapy Response

Somatic mutations in nucleophosmin ( NPM1 ) are key in defining a common subtype of acute myeloid leukemia ( NPM1 -AML), characterized by chromosomal stability and favorable therapeutic responses. However, some patients exhibit a suboptimal response to initial treatment, and relapses are common, highlighting the need for novel biomarkers. Notably, NPM1 and TP53 mutations rarely co-occur in AML, where TP53 mutations correlate with aneuploidy and poor survival outcomes. Here, we present transcriptomic and proteomic evidence of unexpectedly high wild-type (WT) TP53 /p53 expression in a subset of NPM1 -AMLs at baseline. Analyses of the Beat AML cohort indicate that NPM1 -AMLs generally express more TP53 than NPM1 / TP53 -WT AMLs. Among seventy-four NPM1 -AML samples, those with the lowest TP53 co-expression are enriched for downregulated signatures linked to DNA repair, apoptosis, and the cell cycle. By profiling thirty-three primary patient samples using multiplex immunofluorescence staining with single cell-based quantitative digital image analysis, we observed increased p53 expression in NPM1 -mutant cells compared to WT cells. Importantly, patients with primary refractory disease showed low p53 co-expression at diagnosis. These findings suggest that WT-p53 might play a crucial role in the biological and clinical characteristics seen in NPM1 -AML.