The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK⁺ T-cell lymphoma.
The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK⁺ T-cell lymphoma.
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DOI：
10.1186/s12943-015-0324-2
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发表时间：
2015-02-25
期刊：
影响因子：
37.3
通讯作者：
Amin HM
中科院分区：
文献类型：
--
作者：
Vishwamitra D;Curry CV;Alkan S;Song YH;Gallick GE;Kaseb AO;Shi P;Amin HM
I型胰岛素样生长因子受体（IGF-IR）酪氨酸激酶通过与核磷蛋白-间变性淋巴瘤激酶（NPM-ALK）致癌蛋白相互作用促进侵袭性T细胞淋巴瘤亚型的存活。NPM-ALK+ T细胞淋巴瘤表现出比正常人T淋巴细胞高得多的IGF-IR水平。这种淋巴瘤中IGF-IR表达增加的机制尚不清楚。我们假设IGF-IR的上调可能归因于NPM-ALK+ T细胞淋巴瘤中转录机制中固有存在的先前未识别的缺陷。筛选研究显示，NPM-ALK+ T细胞淋巴瘤细胞系和患者原发性肿瘤组织中转录因子Ikaros亚型1（Ik-1）和髓样锌指1（MZF 1）的水平显著低于人T淋巴细胞。荧光素酶分析支持Ik-1和MZF 1抑制IGF-IR基因启动子。ChIP分析表明，这些转录因子与IGF-IR基因启动子内的特异性位点结合。Ik-1或MZF 1在淋巴瘤细胞中的强制表达降低IGF-IR mRNA和蛋白。这种降低与pIGF-IR的下调及其相互作用蛋白IRS-1、AKT和NPM-ALK的磷酸化有关。此外，Ik-1和MZF 1的过表达降低了淋巴瘤细胞的活力、增殖、迁移和非锚定依赖性集落形成。我们的研究结果提供了新的证据，即Ik-1和MZF 1的异常降低通过IGF-IR表达的上调显著促进了NPM-ALK+ T细胞淋巴瘤的发病机制。这些发现可以用来制定新的策略来根除这种淋巴瘤。本文的在线版本（doi：10.1186/s12943-015-0324-2）包含补充材料，可供授权用户使用。
The type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase promotes the survival of an aggressive subtype of T-cell lymphoma by interacting with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein. NPM-ALK+ T-cell lymphoma exhibits much higher levels of IGF-IR than normal human T lymphocytes. The mechanisms underlying increased expression of IGF-IR in this lymphoma are not known. We hypothesized that upregulation of IGF-IR could be attributed to previously unrecognized defects that inherently exist in the transcriptional machinery in NPM-ALK+ T-cell lymphoma. Screening studies showed substantially lower levels of the transcription factors Ikaros isoform 1 (Ik-1) and myeloid zinc finger 1 (MZF1) in NPM-ALK+ T-cell lymphoma cell lines and primary tumor tissues from patients than in human T lymphocytes. A luciferase assay supported that Ik-1 and MZF1 suppress IGF-IR gene promoter. Furthermore, ChIP assay showed that these transcription factors bind specific sites located within the IGF-IR gene promoter. Forced expression of Ik-1 or MZF1 in the lymphoma cells decreased IGF-IR mRNA and protein. This decrease was associated with downregulation of pIGF-IR, and the phosphorylation of its interacting proteins IRS-1, AKT, and NPM-ALK. In addition, overexpression of Ik-1 and MZF1 decreased the viability, proliferation, migration, and anchorage-independent colony formation of the lymphoma cells. Our results provide novel evidence that the aberrant decreases in Ik-1 and MZF1 contribute significantly to the pathogenesis of NPM-ALK+ T-cell lymphoma through the upregulation of IGF-IR expression. These findings could be exploited to devise new strategies to eradicate this lymphoma. The online version of this article (doi:10.1186/s12943-015-0324-2) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.93.9.4181
发表时间：
1996-04-30
影响因子：
11.1
作者：
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