Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes
Abstract
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
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (60)
Matteo Zampini
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Riva
Luca Lanino
3Yale University, New Haven, United States
Elisabetta Sauta
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Rita Antunes Dos Reis
Rosa Maria Andres Ejarque
Haematology, Guy's Hospital & Comprehensive Cancer Centre, King's College, London, United Kingdom
Giulia Maggioni
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Alberto Termanini
4Human Technopole, Milan, Italy
Alessandra Merlotti
2Department of Physics and Astronomy (DIFA) Alma Mater Studiorum—Università di Bologna, Bologna, Italy
Alessia Campagna
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Lorenzo Dall’Olio
Austin Kulasekararaj
22King's College Hospital NHS Foundation Trust, London and King's College London, London, United Kingdom
Michela Calvi
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Clara Di Vito
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Arturo Bonometti
IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
Daoud Rahal
IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
Giorgio Croci
SC Anatomia Patologica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Emanuela Boveri
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Umberto Gianelli
Maurilio Ponzoni
Rossella Caselli
IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
Serena Albertazzi
IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
Gabriele Todisco
Marta Ubezio
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Laura Crisafulli
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Alessandro Frigo
IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
Enrico Lugli
Ettore Mosca
Pamela Acha
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain
Serena Ghisletti
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Francesco Nicassio
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
Armando Santoro
IRCCS Humanitas Research Hospital, Milan
Maria Diez-Campelo
11Hospital Clínico Universitario de Salamanca, Salamanca, Spain
Francesc Sole
8Institut de Recerca Contra la Leucèmia Josep Carreras, Barcelona, Spain
Lionel Adès
Uwe Platzbecker
Valeria Santini
7DMSC University of Florence, AOUC, MDS Unit, Hematology, Florence, Italy
Pierre Fenaux
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
David Sallman
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Guillermo Garcia-Manero
Domenico Mavilio
Daniel Remondini
Gastone Castellani
Saverio D'Amico
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Amer M. Zeidan
Rami Komrokji
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Shahram Kordasti
Francesca Ficara
Matteo Giovanni Della Porta
Antonio Russo
Erica Travaglino
8Pathology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Mattia Delleani
2Train s.r.l., Milan, Italy
Gianluca Asti
Denise Ventura
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Cristina A. Tentori
Alessandro Buizza
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Matteo Brindisi
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Nicole Pinocchio
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Francesco Pesce
31Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy