CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis
CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis
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DOI：
10.1172/jci45851
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Thomas-Tikhonenko, Andrei
中科院分区：
文献类型：
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作者：
Chung, Elaine Y.;Psathas, James N.;Thomas-Tikhonenko, Andrei
PAX 5是一种B细胞特异性转录因子，通过染色体易位在B细胞淋巴瘤亚群中过表达。以前，我们已经表明，激活免疫受体酪氨酸激活基序（ITAM）蛋白和B细胞受体（BCR）信号传导PAX5有助于B淋巴瘤的发生。然而，PAX5对其他致癌转录因子控制的途径的影响尚不清楚。使用MYC诱导的小鼠。在淋巴瘤模型以及MYC转化的人B细胞系中，我们发现PAX 5控制c-MYC蛋白的稳定性和稳态水平。这种启动子非依赖性的c-MYC翻译后调节机制不依赖于ITAM/BCR活性。相反，它是由另一个PAX5靶点CD19通过PI3K-AKT-GSK 3 β轴控制的。因此，CD 19缺陷小鼠的B细胞中的MYC水平急剧降低。相反，在PAX5自发沉默的鼠淋巴瘤中CD19的再表达促进了MYC水平、其关键靶基因的表达、体外细胞增殖和体内总体肿瘤生长。在人类B淋巴瘤中，发现CD19 mRNA水平与MYC激活基因相关。它们也与淋巴瘤患者的总生存率呈负相关，与MYC水平呈负相关。因此，CD 19是B细胞肿瘤中MYC驱动的肿瘤生长的主要BCR非依赖性调节因子。
PAX5, a B cell-specific transcription factor, is overexpressed through chromosomal translocations in a :subset of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activation motif (ITAM) proteins and B cell receptor (BCR) signaling by PAX5 contributes to B-lymphomagenesis. However, the effect of PAX5 on other oncogenic transcription factor-controlled pathways is unknown. Using a MYC-induced murine. lymphoma model as well as MYC-transformed human B cell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels. This promoter-independent, posttranslational mechanism of c-MYC regulation was independent of ITAM/BCR activity. Instead it was controlled by another PAX5 target, CD19, through the PI3K-AKT-GSK3 beta axis. Consequently, MYC levels in B cells from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 in murine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression of its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In human B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC-activated genes. They also negatively correlated with the overall survival of patients with lymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independent regulator of MYC-driven neoplastic growth in B cell neoplasms.