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Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis

Camelia Iancu-Rubin1, Goar Mosoyan1, Kelli Glenn2

  • 1Division of Hematology and Medical Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Experimental Hematology
|December 7, 2013
PubMed

Insights

RG7112, an MDM2 antagonist, causes thrombocytopenia by activating p53. This disrupts megakaryocyte (MK) development through progenitor cell apoptosis and impaired platelet production in mature MKs.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • The tumor suppressor p53 is implicated in megakaryocyte (MK) development.
  • MDM2 is a negative regulator of p53.
  • MDM2 antagonists activate p53.

Purpose of the Study:

  • To investigate the effect of RG7112, an MDM2 antagonist, on normal megakaryocytopoiesis and platelet production.
  • To elucidate the mechanisms underlying RG7112-induced thrombocytopenia.

Main Methods:

  • Administration of RG7112 in vivo to rats and monkeys.
  • In vitro studies using human megakaryocyte progenitor cells.
  • Assessment of MK apoptosis, DNA synthesis, and platelet production.

Main Results:

  • RG7112 administration induced thrombocytopenia in rats and monkeys.
  • In vitro, RG7112 promoted apoptosis of MK progenitor cells.
  • RG7112 impaired DNA synthesis during endomitosis and reduced platelet production in mature MKs.

Conclusions:

  • RG7112-induced p53 activation disrupts normal megakaryocytopoiesis via two distinct mechanisms.
  • These findings explain RG7112-induced thrombocytopenia and highlight the p53-MDM2 loop's role in MK development.

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