title: P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis.
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.
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.|Laboratory of Excellence GR-Ex, Villejuif, France.|Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie.
authors.forename: Emna
authors.initials: E
authors.lastname: Mahfoudhi
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lordier
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Pan
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Roy
authors.affiliation: Départment of Clinical Hematology, Hôpital Henri-Mondor, Créteil, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Roy
authors.affiliation: Flow Cytometry Platform, Gustave Roussy, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.affiliation: Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie.
authors.forename: Salem
authors.initials: S
authors.lastname: Abbes
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Sanofi Oncology, Vitry-sur-Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Debussche
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.|Laboratory of Excellence GR-Ex, Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.|UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.|Gustave Roussy, Villejuif, France.|Laboratory of Excellence GR-Ex, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology / Q000633:toxicity*; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced; D034061:Thrombopoiesis / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D007093:Imidazoles; D007211:Indoles; C574930:MI-219; D010879:Piperazines; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C000593797:SAR405838; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2 inhibitors; apoptosis; megakaryopoiesis; p53; progenitors