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JCI:CD19或成B细胞淋巴瘤治疗新靶点

来源:生物谷 2012-05-09 11:44

B细胞淋巴瘤,通常发生于儿童和成年人,是一种攻击免疫系统中B细胞的癌症类型。近日,费城儿童医院的研究员明确了驱动癌症信号的分子通路。

费城儿童医院肿瘤科研究员Andrei Thomas-Tikhonenko博士说,我们的研究表明如何制定更具体的疗法,能选择性地杀死一类淋巴瘤中的肿瘤细胞。

相关研究在动物细胞和人类细胞培养中进行研究,研究论文发表在Journal of Clinical Investigation杂志上。

一个基因通常会编码产生一种蛋白质,在细胞的生长或监管中发挥重要积极。然而,当该基因发生突变或过量时,通常可以导致癌症发生。该项研究的重点在于被称为MYC基因的一个癌基因,主要研究Myc基因如何推动B细胞淋巴瘤的发生与发展。Myc基因处于较高水平,细胞生长失控,这是癌症的一个标志。

研究人员关注于细胞表面受体CD19的关键作用,他们发现CD19对稳定Myc蛋白来说是绝对必要的。 当Myc基因是稳定的,并处于较高水平时,Myc基因会促使癌症发展。Myc蛋白水平高的患者更可能死于淋巴瘤。

Myc蛋白水平高的患者CD19水平也高,在这项研究中,研究人员描述了一个前所未知的依赖于CD19的分子通路。CD19控制Myc基因通路上的开关。没有CD19的,就没有Myc基因,他补充说,控制通断开关可能代表了治疗淋巴瘤的有力工具。

Thomas-Tikhonenko表示:目前已经有肿瘤的临床试验测试对抗CD19受体的抗体。这种抗体能杀死所有的B细胞,从而削弱免疫系统。他的研究表明了解CD19的信号途径可以使研究人员能够设计一个更具体的治疗方法,能选择性地杀死肿瘤细胞,同时保留健康的B细胞。

他补充说,他的实验室将进一步研究探讨这些分子途径以及如何将研究成果转化为未来抗癌治疗手段。(生物谷:Bioon.com)

CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis

Elaine Y. Chung1, James N. Psathas1, Duonan Yu2, Yimei Li3, Mitchell J. Weiss2,4 and Andrei Thomas-Tikhonenko1,4

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-GSK3β 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.

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