Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and-independent mechanisms

A. Ali, O. Bluteau, K. Messaoudi, A. Palazzo, S. Boukour, L. Lordier, Y. Lecluse, P. Rameau, L. Kraus-Berthier, A. Jacquet-Bescond, H. Lelièvre, S. Depil, P. Dessen, E. Solary, H. Raslova, W. Vainchenker, I. Plo, N. Debili

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    Résumé

    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 cH2AX 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.

    langue originaleAnglais
    Numéro d'articlee738
    journalCell Death and Disease
    Volume4
    Numéro de publication7
    Les DOIs
    étatPublié - 1 juil. 2013

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