Breaking the guardian of the genome: TP53 dysfunction in myeloid neoplasms

Since its discovery more than 40 years ago, TP53 has emerged as the most iconic gene in cancer biology. Early studies of mutant constructs led researchers to misclassify TP53 as an oncogene, a misconception later resolved when wild-type p53 was shown to function as a tumor suppressor. p53 is now widely recognized as the central guardian of genomic integrity, coordinating DNA-damage responses, cell-cycle control, senescence, apoptosis, and metabolic stress adaptation. In myeloid neoplasms, TP53 mutations occur in only ∼10-15% of cases but confer a disproportionately adverse clinical impact marked by resistance to standard therapies and reduced survival. Reflecting this significance, recent iterations of both the World Health Organization and International Consensus Classification have designated TP53-mutated myeloid neoplasms as distinct high-risk entities. In this review, we summarize the biological roles of p53, examine how TP53 gene alterations drive therapeutic resistance in myeloid neoplasms, and compare contemporary classification frameworks, including their limitations and proposed refinements. We also highlight standard and emerging therapeutic strategies aimed specifically at TP53-mutated myeloid neoplasms.