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

作者：Matteo Zampini, E. Riva, L. Lanino, Elisabetta Sauta, Rita Antunes Dos Reis, Rosa Maria Andres Ejarque, G. Maggioni, A. Termanini, Alessandra Merlotti, Alessia Campagna, Lorenzo Dall'olio, A. Kulasekararaj, M. Calvi, C. Di Vito, A. Bonometti, Daoud Rahal, G. Croci, E. Boveri, Umberto Gianelli, Maurilio Ponzoni, Rossella Caselli, Serena Albertazzi, G. Todisco, M. Ubezio, L. Crisafulli, Alessandro Frigo, Enrico Lugli, E. Mosca, P. Acha, S. Ghisletti, F. Nicassio, A. Santoro, M. Díez-Campelo, Francesc Solé, Lionel Adès, U. Platzbecker, V. Santini, Pierre Fenaux, T. Haferlach, D. Sallman, G. Garcia-Manero, Domenico Mavilio, D. Remondini, G. Castellani, S. D'amico, A. Zeidan, R. Komrokji, S. Kordasti, F. Ficara, M. G. Della Porta · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/JCO-24-02394 · 被引用次数：11 · 研究领域：Medicine

PURPOSE Tumor 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 METHODS We 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. RESULTS Biallelic 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 ...