The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Abstract

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor-suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small-molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

Keywords: P53; TP53; acute myeloid leukemia; leukemia; therapy.

FIGURE 1

Relatively lower frequencies of TP53 mutations in leukemia. The frequency of TP53 mutations in human cancer in the (A) MSK-IMPACT study and (B) TCGA is plotted as a percentage. x-axis shows the percentage of samples within that cancer subset that bears TP53 mutations. Mutations in leukemia are annotated in red labeling. TCGA, The Cancer Genome Atlas; MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets

FIGURE 2

The frequency and impact of TP53 mutations in AML. A, Mutations in AML from the TCGA study are shown in this packed bubbles plot. Size of the bubbles represent mutation frequency, which is also noted below gene names. Only the 50 most frequent mutations are represented. B, Donut plot shows the frequency of mutations in TP53 (blue) compared with TP53 wild-type samples (orange) in the TCGA-AML dataset. C. Kaplan-Meier plot showing the overall survival of TCGA-AML patients with TP53 mutations compared with those with wild-type TP53 is shown. x-axis shows time in months and y-axis displays the percent surviving. Statistical differences between the two groups are denoted by log rank t test. D, TP53 mutation frequency in t-AML is shown. AML, acute myeloid leukemia; t-AML, therapy-associated AML; TCGA, The Cancer Genome Atlas

FIGURE 3

Sites of TP53 mutation in all cancers and in AML. A, Pan-cancer analysis of TP53 mutations across TCGA studies showing hotspots. Each vertical line represents a mutation in that region of TP53 with the height of the line indicating the frequency of that particular mutation on the y-axis. B, Lolliplot showing TP53 mutations found in the TCGA AML Study (LAML) Dataset. AML, acute myeloid leukemia; DBD, DNA-binding domain; TAD, trans-activation domain; TCGA, The Cancer Genome Atlas; TET, tetramerization domain