AML chemoresistance: The role of mutant TP53 subclonal expansion and therapy strategy

Abstract

Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized by the proliferation and accumulation of myeloid blast cells in the bone marrow, which eventually lead to hematopoietic failure. Chemoresistance presents as a major burden for therapy of AML patients. p53 is the most important tumor suppressor protein that regulates cellular response to various stress. It is also important for hematopoietic stem cell development and hematopoiesis. Mutation or deletion of TP53 has been found to be linked to cancer progression, therapy-related resistance, and poor prognosis. TP53 mutation occurs in less than 10% of AML patients; however, it represents a subset of AML with therapy resistance and poor outcome. In addition, there is a subgroup of patients with low-frequency TP53 mutations. The percentage ranges from 1% to 3% of all AML patients. These patients have outcomes comparable to those of the high-frequency TP53 mutation patients. TP53-mutated clones isolated from the parental cells exhibit a survival advantage under drug treatment compared with cells with wild-type TP53, and have a higher population of leukemia stem cell (LSC) marker-positive cells, a characteristic of chemo-resistant cells. Therefore, low-frequency TP53 mutation, which is currently underappreciated, is an important prognosis factor for AML patients. Epigenetic drugs, such as hypomethylating agent and histone deacetylase inhibitors, have been found effective in targeting TP53-mutated AML. Histone deacetylase inhibitors can preferentially target the TP53-mutated subpopulation by reactivating p53-targeted genes and by eradicating LSC marker-positive cells. Therefore, combined treatment with epigenetic drugs may represent a new therapeutic strategy for treatments of TP53-mutated AML.