T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.
T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.
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DOI：
10.18632/oncotarget.5418
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Nakamura Y
中科院分区：
文献类型：
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作者：
Alachkar H;Mutonga M;Malnassy G;Park JH;Fulton N;Woods A;Meng L;Kline J;Raca G;Odenike O;Takamatsu N;Miyamoto T;Matsuo Y;Stock W;Nakamura Y
FLT3的功能获得性突变（FLT3- itd）占正常核型急性髓性白血病（AML）的30%，并与不良预后相关。目前的FLT3激酶抑制剂已经进行了广泛的测试，但尚未产生生存效益，新的治疗方法正在等待。在这里，我们发现T-LAK细胞源蛋白激酶（TOPK）是一种在几种类型的癌症中高度表达并与更具侵袭性表型相关的有丝分裂激酶，在AML中表达，而在正常CD34+细胞中不表达，并且TOPK敲低会降低细胞活力并诱导细胞凋亡。用TOPK抑制剂（OTS514）治疗AML细胞导致flt3突变细胞的细胞活力呈剂量依赖性下降，IC50降低，包括从flt3抑制剂治疗后复发的患者获得的原细胞。在mv4 -11移植小鼠模型中，我们发现每天注射7.5 mg/kg静脉注射3周后，小鼠的存活时间明显长于对照组（中位生存期46天vs 29天，P < 0.001）。重要的是，我们确定了TOPK是FLT3- itd和CEBPA调节的激酶，并且调节TOPK的表达或活性导致FLT3表达和CEBPA磷酸化的显著降低。因此，在FLT3-ITD AML中靶向TOPK代表了一种新的治疗AML不良风险亚群的方法。
Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.