Consolaro Francesca, Basso Giuseppe, Ghaem-Magami Sadaf, Lam Eric W-F, Viola Giampietro
Department of Woman's and Child's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
Int J Oncol. 2015 Oct;47(4):1230-40. doi: 10.3892/ijo.2015.3139. Epub 2015 Aug 28.
The Forkhead box protein M1 (FOXM1) is a transcription factor that plays a central role in the regulation of cell cycle, proliferation, DNA repair, and apoptosis. FOXM1 is overexpressed in many human tumors and its upregulation has been linked to high proliferation rates and poor prognosis. We therefore studied the role of FOXM1 in B-lymphoblastic leukemia (B-ALL) in order to understand whether FOXM1 could be a key target for leukemia therapy. RT-PCR and western blot analysis were carried out in a small cohort of pediatric B-ALL patients to evaluate FOXM1 levels. To assess its biological relevance, its expression was down-modulated by transient RNA interference in B-ALL cell lines (REH and NALM-6). Our results show that FOXM1 expression is higher in both B-ALL patients and cell lines when compared to PBMC or normal B-cells (CD19+) from healthy donors. Furthermore, blocking FOXM1 activity in two B-ALL cell lines, by either knockdown or treatment with the FOXM1 inhibitor thiostrepton, causes significant decrease in their cell proliferation. This decrease in cell proliferation was coupled with both an induction of the G2/M cell cycle arrest and with a reduction in the S phase population. Finally, we noted how thiostrepton synergises with chemotherapeutic agents commonly used in B-ALL therapy, thus increasing their efficiency. Therefore our results suggest that FOXM1 is highly expressed in both patients and B-ALL cell lines, and that targeting FOXM1 could be an attractive strategy for leukemia therapy and for overcoming drug resistance.
叉头框蛋白M1（FOXM1）是一种转录因子，在细胞周期调控、增殖、DNA修复和细胞凋亡中发挥核心作用。FOXM1在许多人类肿瘤中过表达，其上调与高增殖率和不良预后相关。因此，我们研究了FOXM1在B淋巴细胞白血病（B-ALL）中的作用，以了解FOXM1是否可能是白血病治疗的关键靶点。对一小群儿童B-ALL患者进行了逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析，以评估FOXM1水平。为了评估其生物学相关性，通过瞬时RNA干扰在B-ALL细胞系（REH和NALM-6）中下调其表达。我们的结果表明，与健康供体的外周血单个核细胞（PBMC）或正常B细胞（CD19+）相比，B-ALL患者和细胞系中的FOXM1表达均较高。此外, 通过敲低或用FOXM1抑制剂硫链丝菌肽处理来阻断两种B-ALL细胞系中的FOXM1活性，会导致其细胞增殖显著降低。这种细胞增殖的降低与G2/M细胞周期阻滞的诱导以及S期细胞群体的减少有关。最后，我们注意到硫链丝菌肽与B-ALL治疗中常用的化疗药物协同作用，从而提高了它们的疗效。因此，我们的结果表明，FOXM1在患者和B-ALL细胞系中均高表达，靶向FOXM1可能是白血病治疗和克服耐药性的一种有吸引力的策略。
