HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?
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Teresa L. Ramos1,2, Luis Ignacio Sánchez-Abarca1,2,3, Alba Redondo1,2, Ángel Hernández-Hernández2,4, Antonio M. Almeida5, Noemí Puig1, Concepción Rodríguez1,2,3, Rebeca Ortega1,2, Silvia Preciado1,2, Ana Rico1,2, Sandra Muntión1,2, José Ramón González Porras1,2, Consuelo Del Cañizo1,2, Fermín Sánchez-Guijo1,2,3
1Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Salamanca, Spain
2Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
3Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain
4Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain
5Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa, Lesboa, Portugal
Consuelo Del Cañizo, email: firstname.lastname@example.org
Keywords: HDAC8, bone marrow-mesenchymal stromal cells, myeloproliferative neoplasm cell lines, apoptosis, myeloproliferative neoplasms
Received: November 30, 2016 Accepted: February 18, 2017 Published: March 07, 2017
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.
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