Unknown

Dataset Information

0

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 ?H2AX 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.

SUBMITTER: Ali A 

PROVIDER: S-EPMC3730430 | BioStudies | 2013-01-01

REPOSITORIES: biostudies

Similar Datasets

2013-06-30 | E-MTAB-1180 | BioStudies
2013-06-30 | E-MTAB-1180 | ArrayExpress
2017-01-01 | S-EPMC5593556 | BioStudies
2015-01-01 | S-EPMC4393337 | BioStudies
2017-01-01 | S-EPMC5791833 | BioStudies
| S-EPMC3681875 | BioStudies
1000-01-01 | S-EPMC5593555 | BioStudies
2017-01-01 | S-EPMC5477609 | BioStudies
2014-01-01 | S-EPMC3949989 | BioStudies
1000-01-01 | S-EPMC4954455 | BioStudies