Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-κB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo.

中文翻译：

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致癌激活和炎症信号的双重靶向增加了骨髓增生性肿瘤的治疗功效。

遗传和功能研究强调了JAK / STAT信号在骨髓增生性肿瘤（MPN）中的核心作用。然而，在MPNs中介导转化的机制尚未完全阐明，临床上使用的JAK抑制剂降低疾病负担或逆转骨髓纤维化的能力有限。在这里，我们显示MPN祖细胞的特征在于通过差异增强剂利用在基因调控中的显着改变，并将核因子κB（NF-κB）信号转导为在MPN的恶性和非恶性细胞中激活的关键途径。BET溴结构域蛋白的抑制作用减弱了体内的NF-κB信号传导并减少了细胞因子的产生。最重要的是，JAK / BET联合抑制可显着降低血清中炎性细胞因子的水平，减轻疾病负担，