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

Abstract

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.

Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting

“…Because of their role in gene transcription, they have the ability to increase the expression of growth-promoting factors and decrease the expression of tumor suppressors . Recently, HDACs have been found to have other nonhistone substrates. − For instance, the knockdown of overexpressed HDAC2 in colorectal cells resulted in the upregulation of the cyclin-dependent kinase inhibitor, p21, independent of p53, supporting the hypothesis that HDAC2 is involved in carcinogenesis . Moreover, numerous studies have demonstrated increased HDAC levels in several cancers compared to normal tissues. ,− …”

“…The United States Food and Drug Administration (FDA) has approved four pan-HDAC inhibitors to date: vorinostat (SAHA), romidepsin (FK228), belinostat (PXD101), and panobinostat (LBH-589) . Pan-HDAC inhibition profiles are associated with adverse side effects such as diarrhea, thrombocytopenia, anemia, and cardiac toxicity. ,,,, Mouse models have highlighted that the selective knockdown of HDAC enzymes can improve therapeutic outcomes, whereas the knockdown of other HDACs results in lethal side effects. For instance, the knockdown studies of HDAC6 and HDAC8 have resulted in an impediment of tumor growth, , whereas the embryonic disruption of specific HDACs (including 1, 2, 3, and 7) in mouse models is associated with lethal outcomes .…”

Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

“…PCI-34051 and NCC-149 were among the first HDAC isozyme-selective inhibitors discovered [16][17][18] . These two aromatic hydroxamate derivatives show high selectivity for human HDAC8 (hHDAC8), an HDAC isozyme that has been shown to be overexpressed in several cancers [19][20][21] and whose mutations can lead to the Cornelia de Lange syndrome [22][23][24] .…”

Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype

“…Nowadays, there are few reports regarding the possibility to target MSCs to hamper cancer progression. However, recently Ramos et al (2017) reported that the inhibition of Histone deacetylases 8 in MSCs derived from myeloproliferative neoplasms selectively decreases their hematopoietic-supporting ability [ 9 ].…”