title: Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis.
abstract: The tumor suppressor p53 is thought to play a role in megakaryocyte (MK) development. To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. This drug has been previously been evaluated in clinical trials of cancer patients where thrombocytopenia was one of the major dose-limiting toxicities. In this study, we demonstrated that administration of RG7112 in vivo in rats and monkeys results in thrombocytopenia. In addition, we identified two distinct mechanisms by which RG7112-mediated activation of p53 affected human megakaryocytopoiesis and platelet production in vitro. RG7112 promoted apoptosis of MK progenitor cells, resulting in a reduction of their numbers and RG7112 affected mature MK by blocking DNA synthesis during endomitosis and impairing platelet production. Together, the disruption of these events provides an explanation for RG7112-induced thrombocytopenia and insight into the role of the p53-MDM2 auto-regulatory loop in normal megakaryocytopoiesis.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: camelia.iancu-rubin@mssm.edu.
authors.forename: Camelia
authors.initials: C
authors.lastname: Iancu-Rubin
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Goar
authors.initials: G
authors.lastname: Mosoyan
authors.affiliation: Department of Preclinical Drug Development and Translational Research, Hoffmann-La Roche, Nutley, NJ, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gordon
authors.affiliation: Department of Preclinical Drug Development and Translational Research, Hoffmann-La Roche, Nutley, NJ, USA.
authors.forename: Gwen L
authors.initials: GL
authors.lastname: Nichols
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010976:Platelet Count; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D034061:Thrombopoiesis / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D048288:Imidazolines; C579783:RG7112; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2