Even in patients with myelodysplastic syndromes (MDS) who don’t have a mutation in tumor protein 53 (p53), the p53 protein might still be dysfunctional, according new research published in the Journal of Clinical Oncology. The discovery has implications for how the disease is classified, what treatments are chosen, and how clinical trials are designed.
The study analyzed a cohort of 6,204 patients with MDS and subsets of patients with available information on RNA sequencing of tumor cells (n=109), high-dimensional phenotype of immune cells (n=77), and multiomics analysis (RNA sequencing and proteomics) on single cells (n=15).
The results showed that nonmutational factors contribute to p53 dysfunction in MDS and that biallelic inactivation of TP53, irrespective of variant allele frequency, was a powerful driver of disease progression. The findings suggest that mono- and biallelic inactivation are different stages occurring by a multihit process during the natural history of the disease, which has implications for the optimal timing of therapeutic interventions in these patients.
The study also identified very-high-risk patients, labeled “MDS with p53 dysfunction,” independent of variant allele frequency. Specifically, these were a subset of MDS (5%) characterized by TP53 wild-type and hyperexpression of abnormal p53 protein in bone marrow progenitors that exhibit dismal outcome. These patients displayed a distinct immune dysregulation involving myeloid-derived inflammation and impaired antigen presentation, which may be a driver of their poor prognosis.
The discovery of p53 dysfunction generated independent of TP53 mutations challenges the conventional characterization of TP53 mutations and 17p deletions as the sole drivers of p53 dysfunction in MDS.
“The recognition of patients with p53 dysfunction is relevant to provide correct disease-risk assessment and interventions, as well as to refine the design of clinical trials,” the authors wrote. “These findings may affect diagnostic processes and patients’ clinical management, advancing precision medicine beyond conventional disease stratification on the basis of clinical features and gene mutations.”
Reference
Zampini M, Riva E, Lanino L, et al. Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes. J Clin Oncol. Published online May 2, 2025. doi:10.1200/JCO-24-02394
