Abstract
Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5–10% of de novo AML, and in 30% of therapy related AML (t-AML). TP53 mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of TP53 mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of TP53 on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.
Highlights
The TP53 gene and its protein was first described in 1979 and has since taken center stage due to an avalanche of research after mutations in this gene were identified as the common denominator in more than 50% of human cancers
If associated with a founding clone, TP53 mutation usually coexists with transcription factors (RUNX1, CEBPA, NPM1) or epigenetic genes (DNMT3A, TET2, IDH1/2) or can be seen as a subclone in the process of clonal evolution triggered by a poly comb pathway of SF3B1, SRSF2 or a signaling mechanism involving JAK2, RAS, FLT3, PTPN11, or BCOR [59,61,114]
Similar results were validated with myelodysplasia and secondary acute myeloid leukemia (AML) patients, where in variant allele frequency (VAF) 40% which predicted complex karyotype and worse OS [119,120]
Summary
The TP53 gene and its protein was first described in 1979 and has since taken center stage due to an avalanche of research after mutations in this gene were identified as the common denominator in more than 50% of human cancers. A mutation in the TP53 gene pronounces the effects of oncogenes leading to the uncontrolled proliferation of tumor cells These mutations are known to give rise to a deleterious gain of function (GOF), a loss of function (LOF) or a non-mutational dysfunction or inactivation of the p53 protein [20,21,22,23]. The p53 network is activated primarily by three mechanisms which maintain an increased concentration of p53 protein This stabilization of higher concentrations of p53 allows for p53 binding to DNA sequences with ensuing transcription of adjacent genes, resulting in inhibition of cell division or cell death. TP53 mutations seem to occur when exposed to carcinogens (environmental factors), oncogenic agents or genotoxic insults This observation further elucidates the robust functionality of p53 in maintaining genomic stability and preventing tumor formation [3]. Despite the understanding of CH having an effect on survival, there are currently no data supporting the screening of asymptomatic patients
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