Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes

• Published in: Journal of clinical oncology Vol. 43; no. 18; pp. 2069 - 2083
• Main Authors: Zampini, Matteo, Riva, Elena, Lanino, Luca, Sauta, Elisabetta, Antunes Dos Reis, Rita, Ejarque, Rosa Maria Andres, Maggioni, Giulia, Termanini, Alberto, Merlotti, Alessandra, Campagna, Alessia, Dall’Olio, Lorenzo, Kulasekararaj, Austin, Calvi, Michela, Di Vito, Clara, Bonometti, Arturo, Rahal, Daoud, Croci, Giorgio, Boveri, Emanuela, Gianelli, Umberto, Ponzoni, Maurilio, Caselli, Rossella, Albertazzi, Serena, Todisco, Gabriele, Ubezio, Marta, Crisafulli, Laura, Frigo, Alessandro, Lugli, Enrico, Mosca, Ettore, Acha, Pamela, Ghisletti, Serena, Nicassio, Francesco, Santoro, Armando, Diez-Campelo, Maria, Solé, Francesc, Ades, Lionel, Platzbecker, Uwe, Santini, Valeria, Fenaux, Pierre, Haferlach, Torsten, Sallman, David, Garcia-Manero, Guillermo, Mavilio, Domenico, Remondini, Daniel, Castellani, Gastone, D'Amico, Saverio, Zeidan, Amer M., Komrokji, Rami, Kordasti, Shahram, Ficara, Francesca, Della Porta, Matteo Giovanni
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health 20.06.2025
• Subjects: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Mutation; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; ORIGINAL REPORTS; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO-24-02394

PURPOSETumor Protein 53 (p53) expressed from gene TP53 is a seminal tumor suppressor. We aimed to characterize mutational and nonmutational mechanisms of p53 dysfunction in myelodysplastic syndromes (MDS) and to investigate their clinical effect.PATIENTS AND METHODSWe 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). An independent validation was performed on 914 patients.RESULTSBiallelic TP53 inactivation was a powerful driver of disease progression and identified high-risk patients, regardless of variant allele frequency. Monoallelic and biallelic inactivation represent disease stages occurring as a multihit process in MDS with TP53 mutations, thus potentially refining the optimal timing of therapeutic interventions in these patients. We identified 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 presented upstream p53 signaling aberrations in Pi3K cascade; RAS, WNT, and NF-KB pathways; and MDM2 gene amplification, together with a downstream dysregulation of p53 targets. MDS with p53 dysfunction displayed a distinct immune dysregulation involving myeloid-derived inflammation and impaired antigen presentation, which may be a driver of their poor prognosis and provide the groundwork for innovative immunotherapies.CONCLUSIONThe identification of nonmutational p53 dysfunction in MDS may lay the foundation for a mechanistic classification of myeloid neoplasms, moving beyond a purely molecular stratification. 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