title: 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.
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Ramos
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Spain.
authors.forename: Luis Ignacio
authors.initials: LI
authors.lastname: Sánchez-Abarca
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Redondo
authors.affiliation: Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.|Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Hernández-Hernández
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa, Portugal.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Almeida
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Puig
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Ortega
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Preciado
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rico
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Muntión
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: José Ramón González
authors.initials: JRG
authors.lastname: Porras
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Del Cañizo
authors.affiliation: Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Spain.
authors.forename: Fermín
authors.initials: F
authors.lastname: Sánchez-Guijo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression; D006410:Hematopoiesis / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: HDAC8; apoptosis and myeloproliferative neoplasms; bone marrow-mesenchymal stromal cells; myeloproliferative neoplasm cell lines