TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

Simple Summary: The TP53 gene encodes the p53 protein, which plays a diverse role in responding to various cellular stresses. p53 consists of several functional domains, including a tetramerization domain for forming heterotetramers and a DNA-binding domain for bindings to p53-responsive elements. The most common mutations in acute myeloid leukemia (AML) occur in the DNA-binding domain of p53. TP53 mutations are associated with a very poor prognosis and define a unique disease subgroup within AML. TP53-mutated AML often shows limited response to conventional chemotherapy and even allogeneic hematopoietic stem cell transplantation. There is an urgent need for novel treatment approaches for patients with TP53-mutated AML, given the frustrating treatment outcomes associated with this condition. Incorporating targeted agents and immunologic therapies into future treatment regimens may offer promising options for patients with TP53-mutated AML. Introduction: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein's DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML. Clinical Implications: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents. Conclusions: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.

Automated summary

The TP53 gene is frequently mutated in various human cancers and is the first tumor suppressor gene discovered. Mutations within the DNA-binding domain of TP53 result in loss of DNA-binding capability of p53 protein. However, the phenotypic landscape of TP53 mutations is complex and presents a significant challenge in developing effective treatment strategies. TP53-mutated AML is associated with poor prognosis and is classified as a distinct subgroup within AML. Current standard treatments are largely ineffective for TP53-mutated AML, and there is an urgent need for novel treatment approaches.