Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.
Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.
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DOI：
10.1016/j.ccell.2017.11.009
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发表时间：
2018-01-08
期刊：
影响因子：
50.3
通讯作者：
Levine RL
中科院分区：
文献类型：
--
作者：
Kleppe M;Koche R;Zou L;van Galen P;Hill CE;Dong L;De Groote S;Papalexi E;Hanasoge Somasundara AV;Cordner K;Keller M;Farnoud N;Medina J;McGovern E;Reyes J;Roberts J;Witkin M;Rapaport F;Teruya-Feldstein J;Qi J;Rampal R;Bernstein BE;Bradner JE;Levine RL
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，介导MPN转化的机制尚不完全清楚，临床上使用的JAK抑制剂在减轻疾病负担或逆转骨髓纤维化方面的能力有限。本研究表明，MPN祖细胞通过差异增强子的利用，其基因调控发生了显著变化，并发现NF-κB信号是MPN恶性和非恶性细胞中激活的关键途径。在体内，抑制BET溴域蛋白可减弱NF-κB信号传导并减少细胞因子的产生。最重要的是，JAK/BET联合抑制可显著降低血清炎症细胞因子水平，减轻疾病负担，并逆转体内骨髓纤维化。Kleppe等人发现骨髓增生性肿瘤（MPN）中JAK2信号异常导致染色质改变，从而促进NF-κ B信号传导。BET抑制剂可降低MPN模型NF-κ b诱导的炎症和骨髓纤维化，且与JAK抑制剂联合治疗效果更好。
Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPN). However, the mechanisms that mediate transformation in MPN 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 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. Kleppe et al. show that aberrant JAK2 signaling in myeloproliferative neoplasm (MPN) leads to chromatin changes that promote NF-κ B signaling. BET inhibitors reduce NF-κB-induced inflammation and bone marrow fibrosis in MPN models, and combination treatment with BET and JAK inhibitors shows improved efficacy.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM
影响因子：
158.5
作者：
Klampfl, Thorsten;Gisslinger, Heinz;Kralovics, Robert
通讯作者：
Kralovics, Robert
影响因子：
3
作者：
Bader, GD;Hogue, CW
通讯作者：
Hogue, CW