P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis
Metrics: PDF 1806 views | HTML 2674 views | ?
Emna Mahfoudhi1,2,3,4,5, Larissa Lordier1,2,3, Caroline Marty1,2,3, Jiajia Pan1,2,3, Anita Roy1,2,3, Lydia Roy6, Philippe Rameau7, Salem Abbes5, Najet Debili1,2,3, Hana Raslova1,2,3, Yunhua Chang1,2,3, Laurent Debussche8, William Vainchenker1,2,3,4, Isabelle Plo1,2,3,4
1INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France
2UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France
3Gustave Roussy, Villejuif, France
4Laboratory of Excellence GR-Ex, Villejuif, France
5Laboratoire d’Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie
6Départment of Clinical Hematology, Hôpital Henri-Mondor, Créteil, France
7Flow Cytometry Platform, Gustave Roussy, Villejuif, France
8Sanofi Oncology, Vitry-sur-Seine, France
Isabelle Plo, email: [email protected]
Keywords: p53, progenitors, MDM2 inhibitors, megakaryopoiesis, apoptosis
Received: January 08, 2016 Accepted: February 23, 2016 Published: March 03, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.