The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F
The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F
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DOI：
10.1038/sj.leu.2405049
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发表时间：
2008-04-01
期刊：
影响因子：
11.4
通讯作者：
Rambaldi, A.
中科院分区：
文献类型：
--
作者：
Guerini, V.;Barbui, V.;Rambaldi, A.
我们研究了ITF 2357，一种新的组蛋白去乙酰化酶抑制剂（HDACi）的抗肿瘤活性，对细胞携带JAK 2（V617 F）突变获得真性红细胞增多症（PV）和原发性血小板增多症（ET）患者以及HEL细胞系。JAK 2（V617 F）突变细胞的克隆形成活性被低浓度的ITF 2357（IC 50 0.001-0.01 μ M）抑制，比抑制缺乏该突变的正常或肿瘤细胞生长所需的浓度低100- 250倍。在这些条件下，ITF 2357允许未突变菌落的生长比突变菌落增加7倍。通过蛋白质印迹，我们发现在HEL细胞中，ITF 2357导致总JAK 2和磷酸化JAK 2（V617 F）以及pSTAT 5和pSTAT 3的消失，但它不影响对照K562细胞系中的野生型JAK 2或STAT蛋白。通过实时PCR，我们发现，暴露于ITF 2357后，JAK 2（V617 F）mRNA在PV患者的粒细胞中未被修饰，而JAK 2的已知靶基因PRV-1基因的表达迅速下调。总之，所提供的数据表明，ITF 2357通过特异性下调JAK 2（V617 F）蛋白并抑制其下游信号传导来抑制携带JAK 2（V617 F）突变的细胞增殖。
We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2(V617F) mutation obtained from polycythemia vera (PV) and essential thrombocythemia ( ET) patients as well as the HEL cell line. The clonogenic activity of JAK2(V617F) mutated cells was inhibited by low concentrations of ITF2357 (IC50 0.001-0.01 mu M), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2(V617F) as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2(V617F) mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2(V617F) mutation through a specific downmodulation of the JAK2(V617F) protein and inhibition of its downstream signaling.