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

Abstract

p53 dysfunction; Myelodysplastic syndromes

Disfunción de p53; Síndromes mielodisplásicos

Disfunció de p53; Síndromes mielodisplàsiques

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 of their poor prognosis and provide the groundwork for innovative immunotherapies. Conclusion The 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

Supported by European Union—Horizon 2020/2023 program and Innovative Health initiative, IHI (GenoMed4All project #101017549 to M.G.D.P.; U.P.; M.D-C.; P.F.; T.H.; G.C.; Synthema project, #1101095530 to M.G.D.P.; G.C.; Synthia project #101172872 to M.G.D.P.; S. DA.; G.C); European Union—Next Generation EU—NRRP M6C2 (Investment 2.1 Enhancement and strengthening of biomedical research in the NHS—Project PNRR-MAD-2022-12376695 and PNRR-MCNT1-2023-12377648 to M.G.D.P); AIRC Foundation (Associazione Italiana per la Ricerca contro il Cancro, Milan Italy—Project #29483 to M.G.D.P.; #26216 to G.C; #26537 to V.S.; #28131 to G.M.; #31589 to E.R.; #24506 to S.G); 5 × 1000 MYNERVA (Myeloid Neoplasms Research Venture AIRC—project #21267 to M.G.D.P); PRIN (Ministry of University & Research, Italy—Project 20229B28PE to M.G.D.P and G.C); Ricerca Finalizzata (Italian Ministry of Health, Italy—Project NET-2018-12365935 to M.G.D.P.; GR-2021-12374166 to C.D.V. and M.U); TRAIN srl, Milan Italy (to S.DA); ISCIII PI23/01103 Umbrella Summa and PI20/00970 Umbrella (to M.D.C.); Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain (PI 23/00007 to F.S; 2021); SGR 00560 Generalitat de Catalunya (to F.S); CERCA Program/Generalitat de Catalunya, Fundació Internacional Josep Carreras (to F.S). SK, RADR and RMAE are supported by the CRUK City of London Center Award [CTRQQR-2021/100004] at KCL.