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The HDAC inhibitor Givinostat modulates key hematopoietic genes in JAK2V617F cells, affecting proliferation, differentiation and apoptosis

ABSTRACT: We investigated the mechanism of action of the HDAC inhibitor Givinostat in JAK2V617F cells. We confirm that the drug inhibits colony formation and proliferation and induces apoptosis at doses 2-3 fold lower in JAK2V617F (HEL, UKE1 and SET2) compared to JAK2 wild type cell lines (K562, KU812, THP1 and KG1). By global gene expression analysis, we observed 293 common genes in HEL and UKE1 modulated at 6 hour by Givinostat (179 up and 114 down), of which 8/8 were validated by RTQ-PCR. 25, 28 and 33 modulated genes are implicated in the regulation of proliferation, apoptosis and hematopoiesis, respectively. Interestingly, 9 genes, known to be deregulated in MPN (myeloproliferative neoplasms) patients cells, were normalized by Givinostat. The hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2V617F cells, and ETS1 was upregulated in all cell lines, at both the RNA and protein levels. Modulation of NFE2 and C-MYB was JAK2 dependent, as shown by use of the JAK2 inhibitor AG490. Finally, we suggest that the inhibition of NFE2 and induction of ETS1, also observed in freshly isolated CD34+ cells from MPN patients, may be at least in part responsible for the observed inhibition of erythroid differentiation by the drug. Overall design: Gene expression profiling, JAK2V617F cell lines, ITF2357. This series of microarray experiments contains the gene expression profiles of independent triplicates of HEL and UKE1 erythroleukemia cell lines bearing the JAK2V617F mutation, before and after ITF2357 treatment. 100 nanograms of total RNA were processed, and fragmented biotin-labelled single-stranded DNA target was hybridized to the GeneChip® Gene 1.0 ST array following the Affymetrix manufacturer's instructions.

INSTRUMENT(S): [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version]

ORGANISM(S): Homo sapiens  

SUBMITTER: Luca Agnelli  




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