Haque Moinul, Li Jing, Huang Yung-Hsing, Almowaled Meaad, Barger Carter J, Karpf Adam R, Wang Peng, Chen Will, Turner Suzanne D, Lai Raymond
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G2R3, Canada.
Electron Microscopy Center, Basic Medical Science College, Harbin Medical University, Harbin 150080, Heilongjiang, China.
Cancers (Basel). 2019 Aug 6;11(8):1119. doi: 10.3390/cancers11081119.
Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.
叉头框M1（FOXM1）是一种致癌转录因子，与实体癌和血液系统癌症的发病机制有关。在本研究中，我们研究了FOXM1在NPM-ALK阳性间变性大细胞淋巴瘤（NPM-ALK + ALCL）中的意义，重点关注其与NPM-ALK的相互作用方式，NPM-ALK是这些肿瘤中的关键致癌驱动因子。FOXM1在NPM-ALK + ALCL细胞系（5/5）、患者样本（21/21）以及NPM-ALK转基因小鼠产生的肿瘤（4/4）中均有表达。FOXM1定位于细胞核，并被证实具有转录活性。使用短发夹RNA（shRNA）和药物（硫链丝菌素）抑制两种NPM-ALK + ALCL细胞中的FOXM1，导致细胞生长和软琼脂集落形成减少，这与细胞凋亡和细胞周期停滞有关。FOXM1在功能上与NPM-ALK相关联，因为FOXM1增强了NPM-ALK/STAT3轴的磷酸化。相反，FOXM1的DNA结合和转录活性依赖于NPM-ALK的表达。进一步的研究表明，这种依赖性取决于FOXM1与与NPM-ALK异二聚化的NPM1的结合以及NPM-ALK的磷酸化状态。总之，我们确定FOXM1是NPM-ALK + ALCL中一种重要的致癌蛋白。我们的结果表明NPM-ALK在细胞核中发挥致癌作用，并阐明了NPM1在NPM-ALK病理生物学中的新作用。
