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Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia.

ABSTRACT: TP53 mutations (TP53mut) in AML patients associate with poor prognosis that may affect therapy and outcome. In addition to TP53 mut patients, TCGA AML patient sequencing data show that there are around 3% of patients have detectable low-frequency TP53mut reads. Importantly, these patients showed worse outcome as compared with the TP53 wild type (TP53wt) patients. We have studied the effect of low-frequency TP53mut in two AML cell lines, OCI-AML2 and MV4-11. Both cells have low-frequency single hotspot TP53mut. Interestingly, the resistant cells derived from both lines have homogeneous TP53mut. TP53mut clones isolated from the parental cells also show increased chemoresistance potential and have higher population of leukemia stem cell (LSC) maker positive cells, a characteristic of chemoresistant cells. When mixed with TP53wt cells, the TP53mut cells show survival advantage suggesting its potential to develop chemoresistance. We previously showed that histone deacetylase inhibitor Romidepsin can re-sensitize chemoresistant cells by eradicating LSC marker positive cells. Here we further show that Romidepsin can reactivate p53 targeted genes which are dysregulated in TP53mut cells and preferentially targets TP53mut subpopulation. Therefore, our study shows that low-frequency TP53mut is linked to chemoresistance and sheds light on therapeutic strategies for treatments on chemoresistance.

SUBMITTER: Yan B

PROVIDER: S-EPMC7597970 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia.

Yan Bowen B Chen Qinwei Q Xu Jianfeng J Li Wei W Xu Bing B Qiu Yi Y

Leukemia 20200127 7

TP53 mutations (TP53mut) in AML patients associate with poor prognosis that may affect therapy and outcome. In addition to TP53 mut patients, TCGA AML patient sequencing data show that there are around 3% of patients have detectable low-frequency TP53mut reads. Importantly, these patients showed worse outcome as compared with the TP53 wild type (TP53wt) patients. We have studied the effect of low-frequency TP53mut in two AML cell lines, OCI-AML2 and MV4-11. Both cells have low-frequency single h ...[more]

PMID: 31988438

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Project description:IntroductionTP53 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 implicationsTo 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.ConclusionsDeveloping 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.

Dataset Information

Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia.

Publications

Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia.

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