Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms
Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms
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鲁索替尼和伏立诺他共同靶向 JAK/STAT 信号通路和组蛋白脱乙酰酶可引发针对骨髓增殖性肿瘤的协同作用
DOI：
10.1007/s10637-019-00794-4
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发表时间：
2019-06
影响因子：
3.4
通讯作者：
Zhou Yuan
中科院分区：
文献类型：
--
作者：
Hao Xing;Xing Wen;Yuan Jiajia;Wang Yingshao;Bai Jiaojiao;Bai Jie;Zhou Yuan
The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibitor vorinostat as a rational combination strategy for MPNs. We tested the combination of ruxolitinib and vorinostat in cells with theJAK2V617F mutation, such as HEL cells, c-Kit+cells fromJAK2V617F transgenic mice and bone marrow mononuclear cells (BMMNCs) from patients with MPN. Our results showed significant synergistic effects of this combination strategy. Cotreatment with ruxolitinib and vorinostat synergistically induced apoptosis, cell cycle arrest and inhibition of the colony-forming capacity of HEL cells by attenuating the JAK/signal transducer and activator of transcription (STAT) and protein kinase-B (AKT) signaling pathways. In particular, cotreatment with ruxolitinib and vorinostat prevented the formation of large colonies of colony-forming unit-granulocyte/erythroid/macrophage/megakaryocytes (CFU-GEMMs) and colony-forming unit-granulocyte/macrophages (CFU-GMs) derived from the BMMNCs of patients with MPN. Taken together, these data provided preclinical evidence that the combination of ruxolitinib and vorinostat is a potential dual-target therapy for patients with MPN.
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影响因子：
28.5
作者：
Talpaz M;Paquette R;Afrin L;Hamburg SI;Prchal JT;Jamieson K;Terebelo HR;Ortega GL;Lyons RM;Tiu RV;Winton EF;Natrajan K;Odenike O;Claxton D;Peng W;O'Neill P;Erickson-Viitanen S;Leopold L;Sandor V;Levy RS;Kantarjian HM;Verstovsek S
通讯作者：
Verstovsek S
使用JAK和PAN级I PI3K抑制剂对骨髓增生性肿瘤的联合治疗。
影响因子：
5.3
作者：
Choong ML;Pecquet C;Pendharkar V;Diaconu CC;Yong JW;Tai SJ;Wang SF;Defour JP;Sangthongpitag K;Villeval JL;Vainchenker W;Constantinescu SN;Lee MA
通讯作者：
Lee MA
骨髓增生性肿瘤的表观遗传异常：新型治疗策略的靶标。
影响因子：
5.7
作者：
Mascarenhas J;Roper N;Chaurasia P;Hoffman R
通讯作者：
Hoffman R
影响因子：
7.3
作者：
Lianbin Yao;N. Mustafa;E.C. Tan;Anders Poulsen;Prachi Singh;Minh-Dao Duong-Thi;J. X. T. Lee;P. M. Ramanujulu;W. Chng;J. Yen;S. Ohlson;B. Dymock
通讯作者：
Lianbin Yao;N. Mustafa;E.C. Tan;Anders Poulsen;Prachi Singh;Minh-Dao Duong-Thi;J. X. T. Lee;P. M. Ramanujulu;W. Chng;J. Yen;S. Ohlson;B. Dymock
影响因子：
20.3
作者：
Wang, Yongchao;Fiskus, Warren;Bhalla, Kapil N.
通讯作者：
Bhalla, Kapil N.