Oncotarget

Research Papers:

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

Teresa L. Ramos, Luis Ignacio Sánchez-Abarca, Alba Redondo, Ángel Hernández-Hernández, Antonio M. Almeida, Noemí Puig, Concepción Rodríguez, Rebeca Ortega, Silvia Preciado, Ana Rico, Sandra Muntión, José Ramón González Porras, Consuelo Del Cañizo _ and Fermín Sánchez-Guijo

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Oncotarget. 2017; 8:28187-28202. https://doi.org/10.18632/oncotarget.15969

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Abstract

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

Correspondence to:

Consuelo Del Cañizo, email: concarol@usal.es

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

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.


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