文章：

口服HDAC抑制剂pracinostat （SB939）与JAK2抑制剂pacritinib （SB1518）在临床前AML模型中有效并具有协同作用

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

原文发布日期：2012-05-04

DOI: 10.1038/bcj.2012.14

类型: Original Article

开放获取: 是

英文摘要：

Accurate lymphoma diagnosis, prognosis and therapy still require additional markers. We explore the potential relevance of microRNA (miRNA) expression in a large series that included all major B-cell non-Hodgkin lymphoma (NHL) types. The data generated were also used to identify miRNAs differentially expressed in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) samples. A series of 147 NHL samples and 15 controls were hybridized on a human miRNA one-color platform containing probes for 470 human miRNAs. Each lymphoma type was compared against the entire set of NHLs. BL was also directly compared with DLBCL, and 43 preselected miRNAs were analyzed in a new series of routinely processed samples of 28 BLs and 43 DLBCLs using quantitative reverse transcription-polymerase chain reaction. A signature of 128 miRNAs enabled the characterization of lymphoma neoplasms, reflecting the lymphoma type, cell of origin and/or discrete oncogene alterations. Comparative analysis of BL and DLBCL yielded 19 differentially expressed miRNAs, which were confirmed in a second confirmation series of 71 paraffin-embedded samples. The set of differentially expressed miRNAs found here expands the range of potential diagnostic markers for lymphoma diagnosis, especially when differential diagnosis of BL and DLBCL is required.

摘要翻译： 

急性髓系白血病（AML）目前采用强化化疗进行治疗，但许多老年患者对此耐受性不佳，因此亟需开发毒性更低、耐受性更佳的有效疗法。FMS样酪氨酸激酶3（FLT3）抑制剂、JAK2抑制剂和组蛋白去乙酰化酶抑制剂（HDACi）已在临床研究中得到验证，但单药疗效有限。研究表明HDACi普拉西诺他治疗AML具有显著疗效，且与JAK2/FLT3抑制剂帕克替尼具有协同作用。这两种化合物不仅能抑制携带JAK2V^617F突变的AML细胞中JAK-信号转导与转录激活因子（STAT）信号通路，还能减弱FLT3信号传导——尤其在FLT3-ITD（内部串联重复）细胞系中。在体外实验中，该联合用药可抑制细胞增殖并促进细胞凋亡。这种协同作用在两种不同AML模型（携带JAK2V617F突变的SET-2巨核细胞性AML小鼠模型和FLT3-ITD驱动的MOLM-13模型）的体内实验中得到验证。普拉西诺他与帕克替尼联用能协同抑制肿瘤生长、减少转移，并根据细胞类型差异协同下调JAK2或FLT信号通路。此外，该联合疗法还能使肿瘤生长引发的多种血浆细胞因子/生长因子/趋化因子水平恢复正常，这为HDACi与JAK2/FLT3抑制剂联合治疗AML患者（特别是携带FLT3或JAK2突变者）提供了理论依据。

原文链接：

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML