HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

Oncotarget 2017 Apr;8(17):28187-28202

Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.

Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment.

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.15969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438642PMC
April 2017
92 Reads

Publication Analysis

Top Keywords

hdac8
9
stromal cells
8
colony formation
8
hematopoietic cells
8
hdac8 inhibition
8
myeloproliferative neoplasms
8
cells
5
mpn
5
verified subsequent
4
stat5 summary
4
summary time
4
decrease protein
4
subsequent decrease
4
expression hdac8
4
increased apoptosis
4
apoptosis malignant
4
linked increased
4
hdac8 linked
4
mrna expression
4
time inhibition
4

Similar Publications