Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia.
Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia.
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使用 OTSSP167 抑制母体胚胎亮氨酸拉链激酶在慢性淋巴细胞白血病中显示出有效的抗白血病作用。
DOI：
10.1038/s41388-018-0333-x
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发表时间：
2018
期刊：
影响因子：
8
通讯作者：
Wang Xin
中科院分区：
文献类型：
--
作者：
Zhang Ya;Zhou Xiangxiang;Li Ying;Xu Yangyang;Lu Kang;Li Peipei;Wang Xin
TP53通路缺陷导致慢性淋巴细胞白血病(CLL)的治疗抵抗和不良临床结果，这是一个没有得到满足的临床需求，几乎没有治疗选择。母体胚胎亮氨酸拉链激酶(Melk)是一种新的癌基因，在有丝分裂过程和干细胞维持中发挥重要作用。OTSSP167是一种针对Melk的口服抑制剂，目前正处于I/II期临床试验，用于晚期乳腺癌和急性髓系白血病患者。然而，到目前为止，还没有关于Melk的致癌作用和OTSSP167在慢性淋巴细胞白血病(CLL)中的作用的研究。以往的研究证实，Melk抑制通过P53信号通路抑制癌细胞存活。因此，我们的目标是确定Melk的生物学功能和OTSSP167在CLL中的治疗潜力。在慢性淋巴细胞性白血病中，Melk基因的高表达与白细胞计数增高、分期、乳酸脱氢酶升高、β-2-MG水平升高、未突变的IGHV、ZAP70阳性、17p13缺失及预后不良有关。根据基因表达谱中的功能丰富分析，缺失或抑制Melk的CLL细胞表现为细胞增殖受损，快速启动的凋亡增加，诱导G2/M期停滞，细胞趋化性减弱，并提高了对氟达拉滨和伊布鲁替尼的敏感性。然而，功能获得试验显示细胞增殖和细胞趋化能力增强。此外，OTSSP167还降低了AKT和ERK1/2的磷酸化，降低了FOXM1的磷酸化，降低了FOXM1、细胞周期蛋白B1和CDK1的表达，而上调了p53和p21的表达。综上所述，Melk是CLL治疗靶点的候选者。OTSSP167在CLL细胞中表现出强大的抗肿瘤活性，突出了一种用于白血病干预的新的基于分子的策略。
TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.