<i>TP53</i>-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition.

Abstract

<i>TP53</i>-mutated acute myeloid leukemia (AML) represents a particularly aggressive and therapeutically refractory subtype of the disease. While recurrent chromosomal abnormalities such as -5/del(5q), -7/del(7q), and del(17p) are well studied in this context, additional co-occurring events remain less well defined. Using the multidimensional Leucegene dataset (~700 primary AML specimens), we identified and comprehensively characterized a distinct subset of <i>TP53</i>-altered AML marked by recurrent deletions on the short arm of chromosome 3 [del(3p), >20% <i>TP53</i>-mutated cases]. These deletions frequently co-occur with del(5q) and encompass several ribosomal protein genes (RPGs), leading to a global down-regulation of the ribosomal network and reduced protein synthesis. We show that this ribosomopathy-like phenotype is most pronounced in <i>TP53</i>-mutated cases with combined RPG deletions on chromosomes 3p and 5q, suggesting a cooperative oncogenic mechanism. Chemical screening identified HSP90 inhibition as a selective vulnerability in AML with low RPG expression. These findings highlight a previously unappreciated <i>TP53</i>-altered AML subset characterized by converging genomic and translational defects and suggest that ribosomal stress may serve as a therapeutic entry point for targeted intervention of this patient subgroup.