p53 biology and reactivation for improved therapy in MDS and AML

(2024) 12:34 Zawacka Biomarker Research https://doi.org/10.1186/s40364-024-00579-9 Biomarker Research Open Access REVIEW p53 biology and reactivation for improved therapy in MDS and AML Joanna E. Zawacka1,2* Abstract Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wildtype and mutant p53 reactivation in the clinical trial setting. Keywords MDS, AML, p53, MDM2, MDM4, p73, Improved therapy Introduction Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are cognate, clonal hematological neoplasms and originate from pre-malignant, mutated hematopoietic stem cells (HSCs) that undergo clonal expansion after selection pressure, in a process called clonal hematopoiesis (CH) [1]. Extensive studies showed HSCs are constricted to the lineage − CD34 + CD38 − CD90 + CD45RA − compartment and bear *Correspondence: Joanna E. Zawacka ; 1 Department of Oncology‑Pathology, Karolinska Institute, Stockholm, Sweden 2 Department of Biochemistry, Laboratory of Biophysics and p53 Protein Biology, Medical University of Warsaw, Warsaw, Poland driver mutations in CH [2]. CH results in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood called leukemic stem cells (Fig. 1a). Clonal hematopoiesis often occurs due to aging and is associated with a higher risk of hematological cancers. The rate of CH progression to hematologic neoplasm is 0.5%—1% per year [3, 4]. During their lifespan, hematopoietic stem cells (HSCs) experience functional decline due to accumulated mutations resulting from increased DNA damage or epigenetic reprogramming. They reside in the bone marrow as a genetically heterogeneous cell population [8]. Some HSCs that acquire somatic mutations in genetic modulators (DNMT3A, TET2, ASXL1) and in signaling molecules (JAK2V617F) gain a competitive © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zawacka B iomarker Research (2024) 12:34 Page 2 of 16 Fig. 1 Origin of hematological neoplasms from clonal hematopoiesis (a) and TP53-mutated clonal hematopoiesis (b). With age, hematopoietic stem cells (HSCs) acquire somatic mutations and the mutated clones are expanded during HSCs renewal. Early genetic events lead to clonal hematopoiesis (CH) and the origin of clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), which have different genetic backgrounds, differ in cytopenia status but possess same variant allele frequencies of VAF ≥ 2%. Among these, CCUS have a higher potential of transformation to myelodysplastic syndrome (MDS) with a range of incidence 18–95%. Fitness variants occurring later, confer a growth advantage in the presence of selective pressures such as inflammation, cytotoxic treatment, radiotherapy, bone marrow microenvironment or aging. The consequent selection of high-risk variants, accumulation of the co-occurring mutations, increase in the VAF > 10% and the co-existing cytopenia are predictive of hematopoietic malignancy development and thus, accelerate the progression to hematological neoplasm; myelodysplastic syndrome (MDS) and MDS/AML. TP53-mutated CH occurs in about 2–6% of cancer patients. TP53-mutated MDS and AML account for up to 13% of all de novo cases. In therapy-related myeloid neoplasm, TP53 gene mutations are present in 20–40% of cases [5]. The model shows the pathogenesis of MDS and AML in hereditary cancer syndromes; Li-Fraumeni syndrome (LFS) with congenital TP53 mutations and Schwachman syndrome (SDS) with congenital mutations in Schwachman–Bodian–Diamond syndrome (SBDS) gene and in therapy-related myeloid neoplasm (t-MN); diseases in which TP53 monoallelic mutations play a role in the progression from CH to myeloid malignancy. The incidence of malignant transformation is higher in the presence of selective pressure as delineated for SDS and t-MN. →  →  → tandem of arrows indicates a multi-step process. Modified from [1, 6, 7]. Created with BioRender.com fitness advantage in the presence of selective pressure and expand resulting in clonal hematopoiesis [9, 10]. MDS and AML originate during CH from clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS), which falls into the category of clonal cytopenia (Fig. 1a). CCUS can be distinguished from CHIP thanks to the advancements in NGS techniques. It represents a continuum with MDS to which it prog (...truncated)