title: Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms.
abstract: Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34(+) cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR 1009, Equipe labellisée Ligue Contre le Cancer, Laboratoire d'Excellence GR-Ex.114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Ali
authors.forename: O
authors.initials: O
authors.lastname: Bluteau
authors.forename: K
authors.initials: K
authors.lastname: Messaoudi
authors.forename: A
authors.initials: A
authors.lastname: Palazzo
authors.forename: S
authors.initials: S
authors.lastname: Boukour
authors.forename: L
authors.initials: L
authors.lastname: Lordier
authors.forename: Y
authors.initials: Y
authors.lastname: Lecluse
authors.forename: P
authors.initials: P
authors.lastname: Rameau
authors.forename: L
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: A
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.forename: H
authors.initials: H
authors.lastname: Lelièvre
authors.forename: S
authors.initials: S
authors.lastname: Depil
authors.forename: P
authors.initials: P
authors.lastname: Dessen
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.forename: H
authors.initials: H
authors.lastname: Raslova
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.forename: I
authors.initials: I
authors.lastname: Plo
authors.forename: N
authors.initials: N
authors.lastname: Debili
mesh_terms: D000107:Acetylation; D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects*; D048708:Cell Growth Processes / Q000502:physiology; D004260:DNA Repair; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D010766:Phosphorylation; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512352:abexinostat