E-MTAB-1180 - Transcription profiling by array of the effect of S78454, a pan histone deacetylase inhibitor, on megakaryopoiesis derived from human CD34+ cells

Status
Released on 30 June 2013, last updated on 3 May 2014
Organism
Homo sapiens
Samples (4)
Array (1)
Protocols (7)
Description
S78454 (Abexinostat, PCI-24781) 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 partially understood. We have tested its effect at doses reached in patients plasma on in vitro megakaryopoiesis derived from human CD34+ cells. When added at day 0 in culture, S78454 inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. This effect only required a short incubation period. When added later on (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet formation. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2 signaling. MK gene profiling revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. Double DNA strand breaks were increased as attested by elevated gH2AX phosphorylation level. Consequently, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, but only partially the defect in proplatelet formation. These results suggest that HDACi induces a thrombocytopenia by a p53 dependent mechanism along MK differentiation and a p53 independent mechanism for proplatelet formation.
Experiment types
transcription profiling by array, co-expression, compound treatment, dye swap, in vitro, replicate
Contact
Citation
Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms. Ali A, Bluteau O, Messaoudi K, Palazzo A, Boukour S, Lordier L, Lecluse Y, Rameau P, Kraus-Berthier L, Jacquet-Bescond A, Lelievre H, Depil S, Dessen P,Solary E, Raslova H, Vainchenker W, Plo I, Debili N. Cell Death Dis 25(4):e738 (2013), Europe PMC 23887629
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-MTAB-1180.idf.txt
Sample and data relationshipE-MTAB-1180.sdrf.txt
Raw data (1)E-MTAB-1180.raw.1.zip
Processed data (1)E-MTAB-1180.processed.1.zip
Array designA-MEXP-2104.adf.txt
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