Abstract

TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.

Highlights

  • Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell (HSC) malignancies characterized by bone marrow dysplasia, ineffective hematopoiesis leading to peripheral blood cytopenia, and by the risk of acute myeloid leukemia (AML) transformation [1]

  • Different clinical studies have uniformly reported a correlation between tumor protein p53 (TP53) mutations and resistance to lenalidomide in del(5q) MDS [93,94], in terms of a reduced response rate, poorer overall survival (OS), the appearance and/or increase of TP53-mutant clones, and a higher risk of AML transformation compared to WT patients [7]

  • In the set of genes recurrently mutated in MDS, alterations of TP53 identify a subgroup of patients with peculiar biological and clinical aspects

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Summary

Introduction

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell (HSC) malignancies characterized by bone marrow dysplasia, ineffective hematopoiesis leading to peripheral blood cytopenia, and by the risk of acute myeloid leukemia (AML) transformation [1]. They are involved in different cellular processes, such as histone modification (e.g., ASXL1, EZH2) and DNA methylation (e.g., TET2, DNMT3A, IDH1, IDH2), signal transduction (e.g., NRAS, JAK2), transcriptional regulation (e.g., RUNX1, TP53), and RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2) [4,5]. In this variety of genes, the Homo sapiens tumor protein p53 (TP53) dysregulation plays a crucial role in MDS phenotype, treatment response, and risk of AML transformation [6,7]. The prognostic value of TP53 and its influence on treatment decision-making is discussed, considering the emerging therapeutic strategies that are currently being developed

Molecular Pathways Activation
TP53 Allelic State and Mutational Burden
TP53 Germline Mutations and Familial MDS Predisposition
TP53 and Karyotype Aberrations
Therapy-Related MDS
Prognosis and Clinical Outcome
Conventional Therapeutic Approaches
Emerging Therapeutic Strategies
Findings
Conclusions
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