Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells
Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells
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DOI：
10.1182/blood-2009-05-222133
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发表时间：
2009-12-03
期刊：
影响因子：
20.3
通讯作者：
Bhalla, Kapil N.
中科院分区：
文献类型：
--
作者：
Wang, Yongchao;Fiskus, Warren;Bhalla, Kapil N.
突变体JAK2V617F酪氨酸激酶（TK）存在于大多数bcr - abl阴性骨髓增殖性肿瘤（mpn）患者中。JAK2V617F通过信号转导和转录激活因子（STAT）、RAS/丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3 (PI3)/AKT通路激活下游信号，赋予MPN造血祖细胞（HPCs）增殖和生存优势。已知用泛组蛋白去乙酰化酶（HDAC）抑制剂panobinostat （PS）治疗可抑制热休克蛋白90的伴侣功能，并诱导转化的HPCs的生长停滞和凋亡。在这里，我们证明了PS处理会耗尽JAK2V617F的自磷酸化、表达和下游信号。PS治疗也破坏了JAK2V617F与hsp90的伴侣结合，促进了JAK2V617F的蛋白酶体降解。PS还能诱导表达jak2v617f的人红白血病HEL92.1.7和Ba/F3-JAK2V617F细胞凋亡。用JAK2 TK抑制剂TG101209治疗可减弱JAK2V617F的自磷酸化作用，并诱导HEL92.1.7和Ba/F3-JAK2V617F细胞凋亡。PS和TG101209共处理进一步降低了JAK/STAT信号，并协同诱导HEL92.1.7和Ba/F3-JAK2V617F细胞凋亡。与正常CD34(+) HPCs相比，TG101209和PS共处理对原代CD34(+) MPN细胞具有更大的细胞毒性。这些体外研究结果表明，HDAC和JAK2V617F抑制剂联合治疗对于治疗JAK2V617F阳性MPN具有潜在价值。（血液。2009;114:5024-5033）
The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN. (Blood. 2009; 114: 5024-5033)