Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells.
Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells.
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DOI：
10.1158/1078-0432.ccr-11-1541
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发表时间：
2011-12-01
期刊：
影响因子：
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通讯作者：
Bhalla KN
中科院分区：
文献类型：
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作者：
Fiskus W;Verstovsek S;Manshouri T;Rao R;Balusu R;Venkannagari S;Rao NN;Ha K;Smith JE;Hembruff SL;Abhyankar S;McGuirk J;Bhalla KN
我们测定了热休克蛋白（hsp）90抑制剂（HI）和/或JAK 2酪氨酸激酶抑制剂（TKI）对表达JAK 2-V617 F的培养小鼠（Ba/F3-JAK 2-V617 F）和人（HEL92.1.7和UKE 1）或原代人CD 34+骨髓增生性肿瘤（MPN）细胞的活性。在暴露于HI AUY 922和/或JAK 2-TKI TG 101209后，测定JAK 2-V617 F、其下游信号传导蛋白以及细胞凋亡的水平。用AUY 922处理诱导JAK 2-V617 F的蛋白酶体降解和消耗，以及减弱JAK 2-V617 F下游的信号传导蛋白，即，磷酸（p）-STAT 5、p-AKT和p-ERK 1/2。AUY 922处理还诱导HEL92.1.7、UKE-1和Ba/F3-hJAK 2-V617 F细胞凋亡。AUY 922和TG 101209的联合处理比单独使用任何一种药物引起更大的信号蛋白消耗，并协同诱导HEL92.1.7和UKE-1细胞的凋亡。与正常造血祖细胞相比，用AUY 922和TG 101209的共处理也诱导了人CD 34 + MPN的显著更多的凋亡。与敏感对照相比，JAK 2-TKI抗性HEL/TGR和UKE 1/TGR细胞对JAK 2-TKI表现出显著更高的IC 50值（p <0.001），这与p-JAK 2、p-STAT 5、p-AKT和Bcl-xL的更高表达相关，但BIM水平降低。与敏感对照不同，HEL/TGR和UKE/TGR细胞对HI AUY 922和17-AAG并行敏感;伴随着p-JAK 2、p-STAT 5、p-AKT和Bcl-xL的显著降低，伴随着BIM的诱导。本文呈现的发现表明，用HI和JAK 2-TKI的共处理对培养的和原代MPN细胞发挥协同活性。另外，用HI处理可以克服人MPN细胞中对JAK 2-TKI的抗性。
We determined the activity of heat shock protein (hsp) 90 inhibitor (HI), and/or JAK2 tyrosine kinase inhibitor (TKI) against JAK2-V617F-expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE1) or primary human CD34+ myeloproliferative neoplasm (MPN) cells. Following exposure to the HI AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined. Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, i.e., phospho (p)-STAT5, p-AKT and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1 and Ba/F3-hJAK2-V617F cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone, and synergistically induced apoptosis of HEL92.1.7 and UKE-1 cells. Co-treatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34+ MPN versus normal hematopoietic progenitor cells. As compared to the sensitive controls, JAK2-TKI-resistant HEL/TGR and UKE1/TGR cells exhibited significantly higher IC50 values for JAK2-TKI (p <0.001), which was associated with higher expression of p-JAK2, p-STAT5, p-AKT and Bcl-xL, but reduced levels of BIM. Unlike the sensitive controls, HEL/TGR and UKE/TGR cells were collaterally sensitive to the HIs AUY922 and 17-AAG; accompanied by marked reduction in p-JAK2, p-STAT5, p-AKT and Bcl-xL, with concomitant induction of BIM. Findings presented here demonstrate that co-treatment with HI and JAK2-TKI exerts synergistic activity against cultured and primary MPN cells. Additionally, treatment with HI may overcome resistance to JAK2-TKI in human MPN cells.