NOTCH is part of the transcriptional network regulating cell growth and survival in mouse plasmacytomas.
NOTCH is part of the transcriptional network regulating cell growth and survival in mouse plasmacytomas.
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DOI：
10.1158/0008-5472.can-07-6555
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Morse HC 3rd
中科院分区：
文献类型：
--
作者：
Shin DM;Shaffer DJ;Wang H;Roopenian DC;Morse HC 3rd
除了浆细胞瘤 (PCT) 的 Myc 激活易位特征外，人们对小鼠自发 B 细胞谱系淋巴瘤发生的遗传因素和信号通路知之甚少。在这里，我们使用高通量定量逆转录 PCR 表征了 PCT、中心母细胞弥漫性大 B 细胞淋巴瘤 (CBL) 和高级脾边缘区 B 细胞淋巴瘤 (MZL++) 的转录谱。 CBL 和 MZL++ 的表达谱非常相似，但与 PCT 的表达谱截然不同。在 PCT 表达水平显着较高的基因中，有一些与 NOTCH 信号传导有关，这一发现得到了微阵列数据的基因集富集分析的支持。为了研究该途径的重要性，通过用 γ-分泌酶抑制剂 (GSI) 处理或转导 MAML1 显性失活突变体，在 PCT 细胞系中阻断 NOTCH 信号传导。这些治疗导致 NOTCH 转录靶标表达减少，并与增殖受损和细胞凋亡增加相关。原代 PCT 中转化浆细胞的 GSI 处理也诱导细胞凋亡。这些结果将NOTCH激活与小鼠PCT发病机制中易位Myc下游的致癌信号通路整合起来，这两条信号通路也与人类多发性骨髓瘤和T细胞淋巴母细胞淋巴瘤的发展有关。
Aside from Myc-activating translocations characteristic of plasmacytomas (PCT), little is known about genetic factors and signaling pathways responsible for the development of spontaneous B-cell lineage lymphomas of mice. Here, we characterized the transcriptional profiles of PCT, centroblastic diffuse large B-cell lymphomas (CBL), and high-grade splenic marginal zone B-cell lymphoma (MZL++) using high-throughput quantitative reverse transcription-PCR. Expression profiles of CBL and MZL++ were strikingly similar and quite unlike that of PCT. Among the genes expressed at significantly higher levels by PCT were a number involved in NOTCH signaling, a finding supported by gene set enrichment analyses of microarray data. To investigate the importance of this pathway, NOTCH signaling was blocked in PCT cell lines by treatment with a γ-secretase inhibitor (GSI) or transduction of a dominant-negative mutant of MAML1. These treatments resulted in reduced expression of NOTCH transcriptional targets in association with impaired proliferation and increased apoptosis. GSI treatment of transformed plasma cells in a primary PCT also induced apoptosis. These results integrate NOTCH activation with oncogenic signaling pathways downstream of translocated Myc in the pathogenesis of mouse PCT, two signaling pathways also implicated in development of human multiple myeloma and T-cell lymphoblastic lymphoma.