P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

// Emna Mahfoudhi 1, 2, 3, 4, 5 , Larissa Lordier 1, 2, 3 , Caroline Marty 1, 2, 3 , Jiajia Pan 1, 2, 3 , Anita Roy 1, 2, 3 , Lydia Roy 6 , Philippe Rameau 7 , Salem Abbes 5 , Najet Debili 1, 2, 3 , Hana Raslova 1, 2, 3 , Yunhua Chang 1, 2, 3 , Laurent Debussche 8 , William Vainchenker 1, 2, 3, 4 , Isabelle Plo 1, 2, 3, 4 1 INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France 2 UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France 3 Gustave Roussy, Villejuif, France 4 Laboratory of Excellence GR-Ex, Villejuif, France 5 Laboratoire d’Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie 6 Départment of Clinical Hematology, Hôpital Henri-Mondor, Créteil, France 7 Flow Cytometry Platform, Gustave Roussy, Villejuif, France 8 Sanofi Oncology, Vitry-sur-Seine, France Correspondence to: Isabelle Plo, email: isabelle.plo@gustaveroussy.fr Keywords: p53, progenitors, MDM2 inhibitors, megakaryopoiesis, apoptosis Received: January 08, 2016     Accepted: February 23, 2016     Published: March 03, 2016 ABSTRACT TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.