Abstract
Purpose. Tumor Protein 53(p53) expressed from gene TP53 is a seminal tumor suppressor. We aimed to characterise mutational and non-mutational mechanisms of p53 dysfunction in myelodysplastic syndromes(MDS) and to investigate their clinical effect.
Methods. We analysed a cohort of 6,204 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 multi-omics analysis(RNA-sequencing and proteomics) on single cells(n=15). An independent validation was performed on 914 patients.
Results. Bi-allelic TP53 inactivation was a powerful driver of disease progression and identified high-risk patients, regardless of variant allele frequency. Mono-allelic and bi-allelic inactivation represent disease stages occurring as a multi-hit 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%) characterised by TP53 wild-type and hyperexpression of abnormal p53 protein in bone marrow progenitors, that exhibit dismal outcome. These patients presented up-stream p53 signalling 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 non-mutational 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
Methods. We analysed a cohort of 6,204 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 multi-omics analysis(RNA-sequencing and proteomics) on single cells(n=15). An independent validation was performed on 914 patients.
Results. Bi-allelic TP53 inactivation was a powerful driver of disease progression and identified high-risk patients, regardless of variant allele frequency. Mono-allelic and bi-allelic inactivation represent disease stages occurring as a multi-hit 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%) characterised by TP53 wild-type and hyperexpression of abnormal p53 protein in bone marrow progenitors, that exhibit dismal outcome. These patients presented up-stream p53 signalling 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 non-mutational 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
| Original language | English |
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| Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology |
| Publication status | Accepted/In press - 20 Mar 2025 |