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Decitabine and Melphalan Fail to Reactivate p73 in p53 Deficient Myeloma Cells

Pierre-Samuel Gillardin1, Géraldine Descamps2, Sophie Maiga3

  • 1CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44007 Nantes, France. pierre.gillardin@etu.univ-nantes.fr.

International Journal of Molecular Sciences
|January 4, 2018
PubMed

Insights

Activating p73 to bypass TP53 deficiency in multiple myeloma (MM) is not feasible. TP73 is silenced by methylation in TP53-deficient MM cells, and drug combinations failed to induce sufficient p73 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • TP53 deficiency is a significant challenge in multiple myeloma (MM) treatment.
  • Targeting TP53 directly is not pharmacologically possible.
  • The p53 family member p73 is underexplored in MM.

Purpose of the Study:

  • To investigate the potential of activating p73 as a therapeutic strategy in MM.
  • To assess TP73 methylation and expression in MM cell lines with varying TP53 status.

Main Methods:

  • Analysis of TP73 expression in 47 human myeloma cell lines (HMCLs) using microarray data.
  • Quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) to assess TP73 expression.
  • Evaluation of TP73 methylation and response to decitabine and alkylating agents.

Main Results:

  • TP73 showed weak expression, predominantly in TP53 wild-type HMCLs (p = 0.0029).
  • TP73 was expressed in 57% of TP53 wild-type HMCLs versus 11% of TP53-abnormal HMCLs (p = 0.0463).
  • Decitabine increased TP73 expression in TP53-deficient cells, but not to significant protein levels; alkylating drugs showed limited efficacy.

Conclusions:

  • TP73 is silenced by methylation in TP53-deficient MM cells.
  • Decitabine and melphalan combination therapy is not a promising strategy for inducing p73 and overcoming TP53 deficiency in MM.
Keywords:
CpG methylationalkylating drugsdecitabinemultiple myelomap53p73

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