Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes
Por:
Zampini, M, Riva, E, Lanino, L, Sauta, E, Dos Reis, RA, Ejarque, RMA, Maggioni, G, Termanini, A, Merlotti, A, Campagna, A, Dall'Olio, L, Kulasekararaj, A, Calvi, M, Di Vito, C, Bonometti, A, Rahal, D, Croci, G, Boveri, E, Gianelli, U, Ponzoni, M, Caselli, R, Albertazzi, S, Todisco, G, Ubezio, M, Crisafulli, L, Frigo, A, Lugli, E, Mosca, E, Acha, P, Ghisletti, S, Nicassio, F, Santoro, A, Diez-Campelo, M, Francesc Solé, Ades, L, Platzbecker, U, Santini, V, Fenaux, P, Haferlach, T, Sallman, D, Garcia-Manero, G, Mavilio, D, Remondini, D, Castellani, G, D'Amico, S, Zeidan, AM, Komrokji, R, Kordasti, S, Ficara, F and Della Porta, MG
Publicada:
20 jun 2025
Ahead of Print:
2 may 2025
Resumen:
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
Filiaciones:
Zampini, M:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Riva, E:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Lanino, L:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Humanitas Univ, Dept Biomed Sci, Pieve Emanuele Milan, Italy
Sauta, E:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Dos Reis, RA:
Kings Coll London, Guys Hosp, Haematol, London, England
Kings Coll London, Comprehens Canc Ctr, London, England
Ejarque, RMA:
Kings Coll London, Guys Hosp, Haematol, London, England
Kings Coll London, Comprehens Canc Ctr, London, England
Maggioni, G:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Termanini, A:
Univ Bologna, Dept Phys & Astron, Bologna, Italy
Merlotti, A:
Kings Coll Hosp NHS Fdn Trust, NIHR Wellcome Kings Clin Res Facil, London, England
Campagna, A:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Dall'Olio, L:
Kings Coll Hosp NHS Fdn Trust, NIHR Wellcome Kings Clin Res Facil, London, England
Kulasekararaj, A:
Univ Milan, Dept Med Biotechnol & Translat Med BioMeTra, Milan, Italy
Calvi, M:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Fdn IRCCS Ca Granda Osped Maggiore Policlin, SC Anat Patol, Milan, Italy
Di Vito, C:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Fdn IRCCS Ca Granda Osped Maggiore Policlin, SC Anat Patol, Milan, Italy
Bonometti, A:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Humanitas Univ, Dept Biomed Sci, Pieve Emanuele Milan, Italy
Rahal, D:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Croci, G:
Fdn IRCCS Policlin San Matteo, Pavia, Italy
Boveri, E:
Univ Milan, Dept Hlth Sci, Milan, Italy
Gianelli, U:
IRCCS San Raffaele Sci Inst, Pathol Unit, Milan, Italy
Caselli, R:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Albertazzi, S:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Todisco, G:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Humanitas Univ, Dept Biomed Sci, Pieve Emanuele Milan, Italy
Ubezio, M:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Crisafulli, L:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
CNR, Inst Genet & Biomed Res, Milan Unit, Milan, Italy
Frigo, A:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Fdn IRCCS Ca Granda Osped Maggiore Policlin, SC Anat Patol, Milan, Italy
Lugli, E:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Mosca, E:
Natl Res Council ITB CNR, Inst Biomed Technol, Segrate, Italy
Acha, P:
Vall dHebron Inst Oncol VHIO, Expt Hematol, Barcelona, Spain
Ghisletti, S:
European Inst Oncol IRCCS, Dept Expt Oncol, IEO, Milan, Italy
Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy
Nicassio, F:
Fdn Ist Italiano Tecnol, Ctr Genom Sci IIT SEMM, Milan, Italy
Santoro, A:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Diez-Campelo, M:
Hosp Univ Salamanca, Hematol Dept, Salamanca, Spain
Francesc Solé:
Josep Carreras Leukaemia Res Inst IJC, Myelodysplast Syndromes Res Grp, Barcelona, Spain
Ades, L:
Univ Paris Cite, Hop St Louis, Paris, France
Platzbecker, U:
Univ Hosp Leipzig, Leipzig, Germany
Santini, V:
Univ Florence, Florence, Italy
Fenaux, P:
Univ Paris Cite, Hop St Louis, Paris, France
Haferlach, T:
MLL Munich Leukemia Lab, Munich, Germany
Sallman, D:
H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL USA
Garcia-Manero, G:
Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA
Mavilio, D:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Fdn IRCCS Ca Granda Osped Maggiore Policlin, SC Anat Patol, Milan, Italy
Remondini, D:
Kings Coll Hosp NHS Fdn Trust, NIHR Wellcome Kings Clin Res Facil, London, England
Castellani, G:
Univ Bologna, Dept Med & Surg Sci DIMEC, Bologna, Italy
IRCCS Azienda Osped Univ Bologna, Bologna, Italy
D'Amico, S:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Train Srl, Milan, Italy
Zeidan, AM:
Yale Sch Med, Dept Internal Med, Hematol, New Haven, CT USA
Komrokji, R:
H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL USA
Kordasti, S:
Kings Coll London, Guys Hosp, Haematol, London, England
Kings Coll London, Comprehens Canc Ctr, London, England
Univ Politecn Marche, Hematol Dept, DISCLIMO, Ancona, Italy
Univ Politecn Marche, Stem Cell Transplant Unit, DISCLIMO, Ancona, Italy
Ficara, F:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
CNR, Inst Genet & Biomed Res, Milan Unit, Milan, Italy
Della Porta, MG:
IRCCS Humanitas Res Hosp, Rozzano Milan, Italy
Humanitas Univ, Dept Biomed Sci, Pieve Emanuele Milan, Italy
Green Submitted, hybrid
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