Myc suppression of Nfkb2 accelerates lymphomagenesis.
Myc suppression of Nfkb2 accelerates lymphomagenesis.
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DOI：
10.1186/1471-2407-10-348
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发表时间：
2010-07-02
期刊：
影响因子：
3.8
通讯作者：
Cleveland JL
中科院分区：
文献类型：
--
作者：
Keller U;Huber J;Nilsson JA;Fallahi M;Hall MA;Peschel C;Cleveland JL
c-Myc表达失调是几种人类癌症的标志，其中它促进增殖和侵袭性肿瘤表型。Myc过表达与Rel/NF-κB活性降低相关，Rel/NF-κ B是控制免疫应答、细胞存活和转化的转录因子，并且在癌症中经常发生改变。在淋巴恶性肿瘤中，Rel/NF-κB家族成员NF-κ B2通过染色体易位或缺失而改变，并且NF-κB2的C末端锚蛋白结构域的缺失增强淋巴细胞增殖。评估癌前Eμ-Myc转基因B细胞、Eμ-Myc淋巴瘤和人伯基特淋巴瘤样品的Nfkb 2表达。Nfkb 2对Myc驱动的细胞凋亡、增殖和淋巴瘤发生的贡献在体内进行了遗传学测试。在此我们报道了Myc癌蛋白在体外抑制小鼠原代成纤维细胞和B细胞中Nfkb 2的表达，以及在体内抑制人Burkitt淋巴瘤（BL）的Eμ-Myc转基因小鼠模型中Nfkb 2的表达。Myc对NFKB 2的抑制也在原发性人BL中得到证实。启动子-报告基因分析表明Myc介导的Nfkb 2抑制发生在转录水平。在体内测试了Nfkb 2对Myc驱动的淋巴瘤发生的贡献，其中Nfkb 2的缺失显示通过损害Myc的凋亡反应来加速Eμ-Myc转基因小鼠中的淋巴瘤发展。Nfkb 2被c-Myc抑制并利用Myc驱动的淋巴瘤发生。因此，这些数据将Myc驱动的淋巴瘤发生与非经典NF-κB途径联系起来。
Deregulated c-Myc expression is a hallmark of several human cancers where it promotes proliferation and an aggressive tumour phenotype. Myc overexpression is associated with reduced activity of Rel/NF-κB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-κB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-κB2 augments lymphocyte proliferation. Precancerous Eμ-Myc-transgenic B cells, Eμ-Myc lymphomas and human Burkitt lymphoma samples were assessed for Nfkb2 expression. The contribution of Nfkb2 to Myc-driven apoptosis, proliferation, and lymphomagenesis was tested genetically in vivo. Here we report that the Myc oncoprotein suppresses Nfkb2 expression in vitro in primary mouse fibroblasts and B cells, and in vivo in the Eμ-Myc transgenic mouse model of human Burkitt lymphoma (BL). NFKB2 suppression by Myc was also confirmed in primary human BL. Promoter-reporter assays indicate that Myc-mediated suppression of Nfkb2 occurs at the level of transcription. The contribution of Nfkb2 to Myc-driven lymphomagenesis was tested in vivo, where Nfkb2 loss was shown to accelerate lymphoma development in Eμ-Myc transgenic mice, by impairing Myc's apoptotic response. Nfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-κB pathway.
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