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

Bowen Yan1, Qinwei Chen1,2, Jianfeng Xu3,4

  • 1Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.

Leukemia
|January 29, 2020
PubMed

Insights

Low-frequency TP53 mutations in acute myeloid leukemia (AML) are linked to chemoresistance and poor outcomes. The drug Romidepsin shows promise in re-sensitizing resistant cells by targeting these TP53-mutated cells.

Area of Science:

  • Hematology
  • Cancer Biology
  • Genetics

Background:

  • TP53 mutations (TP53mut) in acute myeloid leukemia (AML) patients are associated with poor prognosis.
  • A subset of AML patients (around 3%) exhibit low-frequency TP53mut reads, correlating with worse outcomes compared to TP53 wild-type (TP53wt) patients.

Purpose of the Study:

  • To investigate the impact of low-frequency TP53 mutations on chemoresistance in AML.
  • To explore the therapeutic potential of Romidepsin in overcoming chemoresistance driven by TP53 mutations.

Main Methods:

  • Studied the effect of low-frequency TP53mut in two AML cell lines (OCI-AML2 and MV4-11).
  • Isolated and analyzed TP53mut clones for chemoresistance and leukemia stem cell (LSC) marker expression.
  • Assessed the survival advantage of TP53mut cells when co-cultured with TP53wt cells.
  • Evaluated the efficacy of Romidepsin in re-sensitizing chemoresistant cells and reactivating p53-targeted genes.

Main Results:

  • Homogeneous TP53mut was observed in chemoresistant cell lines derived from parental cells with low-frequency TP53mut.
  • TP53mut clones exhibited increased chemoresistance and a higher proportion of LSC marker-positive cells.
  • TP53mut cells demonstrated a survival advantage over TP53wt cells, indicating potential for chemoresistance development.
  • Romidepsin re-sensitized chemoresistant cells, eradicated LSC marker-positive cells, reactivated p53-targeted genes, and preferentially targeted TP53mut subpopulations.

Conclusions:

  • Low-frequency TP53 mutations are a significant factor contributing to chemoresistance in AML.
  • Romidepsin is a potential therapeutic strategy for treating chemoresistant AML, particularly in patients with TP53 mutations.

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