Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling
Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling
复制标题
DOI：
10.1111/j.1365-2141.2008.07053.x
复制
发表时间：
2008-05-01
影响因子：
6.5
通讯作者：
Rowntree, Clare
中科院分区：
文献类型：
--
作者：
Al Shaer, Laila;Walsby, Elisabeth;Rowntree, Clare
fms样酪氨酸激酶3基因（FLT3）的激活突变发生在大约三分之一的急性髓性白血病（AML）患者中，并且预测预后较差。热休克蛋白90 （Hsp90）是一种分子伴侣，经常被癌细胞用来稳定突变的癌蛋白。突变的FLT3在原发性AML细胞中有Hsp90伴发，而未突变的FLT3则没有，这使得Hsp90抑制剂具有潜在的治疗作用。本研究表明，17-烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG）抑制Hsp90对表达突变FLT3的原代AML细胞具有细胞毒性。抑制Hsp90可改变原代AML细胞的下游信号传导作用，破坏Janus激酶-信号转导和转录激活因子（JAK-STAT）、丝裂原活化蛋白激酶和磷脂酰肌醇3/AKT信号通路。用17-AAG和阿糖胞苷共同治疗原细胞在大约50%的AML病例中产生了协同或附加效应。我们的研究结果证实，Hsp90是治疗AML的有效分子靶点。在常规AML治疗的同时抑制Hsp90可能对那些预后不良的FLT3突变疾病患者有特别的益处。
Activating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.