FOXM1 is a therapeutic target for high-risk multiple myeloma.
FOXM1 is a therapeutic target for high-risk multiple myeloma.
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DOI：
10.1038/leu.2015.334
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发表时间：
2016-04
期刊：
影响因子：
11.4
通讯作者：
Janz S
中科院分区：
文献类型：
--
作者：
Gu C;Yang Y;Sompallae R;Xu H;Tompkins VS;Holman C;Hose D;Goldschmidt H;Tricot G;Zhan F;Janz S
转录因子叉头盒M1（FOXM1）是实体癌中一种有效的癌蛋白，但其在恶性浆细胞肿瘤如多发性骨髓瘤（MM）中的作用尚不清楚。我们分析了公开的MM数据集，发现FOXM1的过表达在一个新诊断病例的子集（约15%）中显示出较差的结果，特别是基于全局基因表达变化的高危疾病患者。使用人骨髓瘤细胞系（HMCL）作为主要实验模型系统的后续研究表明，FOXM1的强制表达增加了骨髓瘤细胞的生长、存活和克隆形成，而FOXM1的敲除则消除了这些特征。与此一致，FOXM1的组成性上调促进了实验室小鼠中的HMCL异种移植物，而FOXM1的诱导性敲低导致生长抑制。在HMCL和骨髓瘤患者样本中，细胞周期蛋白依赖性激酶6（CDK6）和NIMA相关激酶2（NEK2）的表达与FOXM1共调节，表明这3种基因在遗传网络中相互作用，可能有助于靶向小药物抑制剂，用于骨髓瘤治疗和预防的新方法。这些结果确立了FOXM1作为高风险骨髓瘤基因，并为FOXM1靶向治疗的设计和测试提供了支持，特别是针对FOXM1High骨髓瘤子集。
The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM datasets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive up-regulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was co-regulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these 3 genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1High subset of myeloma.