Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, China.
School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Oncogene. 2018 Oct;37(41):5520-5533. doi: 10.1038/s41388-018-0333-x. Epub 2018 Jun 12.
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.
TP53 通路缺陷导致慢性淋巴细胞白血病（CLL）的治疗耐药和不良临床结局，这是一种未满足的临床需求，治疗选择有限。母系胚胎亮氨酸拉链激酶（MELK）是一种新型致癌基因，在有丝分裂进展和干细胞维持中发挥关键作用。OTSSP167 是一种口服靶向 MELK 的抑制剂，目前正在晚期乳腺癌和急性髓系白血病患者中进行 I/II 期临床试验。然而，迄今为止，尚无关于 MELK 的致癌作用以及 OTSSP167 在慢性淋巴细胞白血病（CLL）中的作用的研究。先前的研究证实，MELK 抑制通过 p53 信号通路破坏癌细胞的存活。因此，我们旨在确定 MELK 的生物学功能和 OTSSP167 在 CLL 中的治疗潜力。在此，观察到 CLL 细胞中 MELK 的过表达，并且与更高的白细胞计数、晚期阶段、升高的 LDH、增加的β2-MG 水平、未突变的 IGHV、阳性 ZAP-70、17p13 缺失和 CLL 患者的预后不良相关。根据基因表达谱的功能富集分析，CLL 细胞中 MELK 的耗竭或抑制表现出受损的细胞增殖、增强的快速起始凋亡、诱导的 G2/M 期阻滞、减弱的细胞趋化性和促进对氟达拉滨和伊布替尼的敏感性。然而，功能获得性测定显示细胞增殖和细胞趋化性增加。此外，OTSSP167 治疗降低了 AKT 和 ERK1/2 的磷酸化。它降低了 FoxM1 磷酸化、FoxM1、cyclin B1 和 CDK1 的表达，同时上调了 p53 和 p21 的表达。总之，MELK 可作为 CLL 的治疗靶标候选物。OTSSP167 在 CLL 细胞中表现出强大的抗肿瘤活性，突出了一种基于新型分子的白血病干预策略。
