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

Bowen Yan, Qinwei Chen, Jianfeng Xu, Wei Li, Bing Xu, Yi Qiu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1816-1827
Number of pages12
Issue number7
StatePublished - Jul 1 2020

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research


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