Ramos Teresa L, Sánchez-Abarca Luis Ignacio, Redondo Alba, Hernández-Hernández Ángel, Almeida Antonio M, Puig Noemí, Rodríguez Concepción, Ortega Rebeca, Preciado Silvia, Rico Ana, Muntión Sandra, Porras José Ramón González, Del Cañizo Consuelo, Sánchez-Guijo Fermín
Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Spain.
Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain.
Oncotarget. 2017 Apr 25;8(17):28187-28202. doi: 10.18632/oncotarget.15969.
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.
组蛋白去乙酰化酶（HDACs）参与表观遗传调控，其异常表达已在骨髓增殖性肿瘤（MPN）中得到证实。HDAC8抑制已被证明可抑制MPN造血细胞中的JAK2/STAT5信号传导。然而，HDAC8在骨髓间充质基质细胞（BM-MSC）中的表达作用尚未得到评估。在当前工作中，我们描述了与健康供体来源的间充质干细胞（HD-MSC）相比，HDAC8在JAK-2阳性MPN的间充质干细胞中显著过表达。使用选择性HDAC8抑制剂（PCI34051），我们证实HDAC8蛋白和mRNA表达的随后降低与恶性间充质干细胞凋亡增加有关，而对正常间充质干细胞没有影响。此外，MPN-MSC中HDAC8的抑制还通过增加JAK2+造血细胞的凋亡、细胞周期停滞和集落形成，降低了它们维持肿瘤性造血的能力。使用不同MPN细胞系的机制研究表明，PCI34051诱导它们的凋亡，当与JAK2V617F-MSC共培养时凋亡增强，降低它们的集落形成以及STAT3和STAT5的磷酸化。总之，我们首次表明，抑制JAK2+ MPN患者间充质干细胞中的HDAC8可选择性降低其造血支持能力，这表明HDAC8可能是这种情况下的潜在治疗靶点，不仅作用于造血细胞，还作用于恶性微环境。
