Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.
Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.
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FOXM1 上调导致骨髓瘤药物敏感性降低
DOI：
10.1186/s12885-018-5015-0
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发表时间：
2018-11-21
期刊：
影响因子：
3.8
通讯作者：
Janz S
中科院分区：
文献类型：
--
作者：
Gu C;Jing X;Holman C;Sompallae R;Zhan F;Tricot G;Yang Y;Janz S
先前的研究证实了转录因子叉头盒M1 （FOXM1）在新诊断的多发性骨髓瘤（nMM）高危亚群的生物学和预后中的参与，本研究评估了FOXM1基因表达是否在复发性多发性骨髓瘤（rMM）患者的肿瘤复发中进一步上调。还评估了FOXM1水平升高降低骨髓瘤细胞对常用骨髓瘤药物（如蛋白酶体抑制剂硼替佐米（Bz）和DNA插入剂阿霉素（Dox））敏感性的假设。使用基因表达微阵列作为测量工具，对来自nMM和rMM患者的88对骨髓瘤样本中的FOXM1信息进行了评估。鉴定差异基因表达的来源，并使用统计方法进行离群分析。两种独立的人骨髓瘤细胞系（hcls）含有正常水平的FOXM1 （FOXM1N）或升高水平的慢病毒编码FOXM1 (FOXM1Hi)，以确定FOXM1依赖性的细胞增殖、存活、外排泵活性和药物敏感性的变化。Western blotting检测视网膜母细胞瘤（Rb）蛋白水平。88例rMM患者中有61例（69%）FOXM1表达上调，其中4例患者FOXM1表达峰值升高20倍。以FOXM1N骨髓瘤为对照，FOXM1Hi骨髓瘤细胞中FOXM1水平升高引起体外对Bz（1.9-5.6倍）和Dox（1.5-2.9倍）的部分耐药。使用小鼠骨髓瘤异种移植在体内证实FOXM1Hi细胞对Bz的敏感性降低。FOXM1依赖于总Rb和磷酸化Rb的调控与骨髓瘤的工作模型一致，表明FOXM1控制染色体不稳定性（CIN）和e2f依赖的增殖，其机制分别涉及与NIMA相关激酶2 （NEK2）和细胞周期蛋白依赖激酶6 （CDK6）的相互作用。这些发现增强了我们对骨髓瘤中新兴的FOXM1遗传网络的理解，并为使用小药物CDK和NEK2抑制剂治疗FOXM1-NEK2和CDK4/6-Rb-E2F通路提供了临床前支持。临床研究有必要评估这种方法是否可以克服FOXM1Hi骨髓瘤的耐药，从而改善转录因子高水平表达的患者的预后。本文的在线版本（10.1186/s12885-018-5015-0）包含补充内容，仅供授权用户使用。
Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9–5.6 fold) and Dox (1.5–2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels. The online version of this article (10.1186/s12885-018-5015-0) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
通讯作者：
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影响因子：
20.3
作者：
Bergsagel, PL;Kuehl, WM;Shaughnessy, J
通讯作者：
Shaughnessy, J
影响因子：
11.4
作者：
Gu C;Yang Y;Sompallae R;Xu H;Tompkins VS;Holman C;Hose D;Goldschmidt H;Tricot G;Zhan F;Janz S
通讯作者：
Janz S
影响因子：
64.5
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通讯作者：
Mitsiades CS
影响因子：
20.3
作者：
Keats, Jonathan J.;Chesi, Marta;Bergsagel, P. Leif
通讯作者：
Bergsagel, P. Leif