BCL10高表达与MALT淋巴瘤发生分子机制的探讨

目的:运用EμSR-BCL10转基因小鼠模型研究BCL10高表达致黏膜相关淋巴组织(MALT)淋巴瘤的分子机制.方法:用IgM+/CD21 lugh/CD23 low荧光标记的抗体染色后进行流式细胞仪分析MZ B细胞；用CD43和CD23磁珠抗体双阴性分离方法获得MZ B细胞并用于体外增殖刺激实验；使用anti-IgM体内注射法研究BCL10体内抗凋亡.结果:MZB细胞增生与BCL10蛋白表达水平存在量效关系.细胞增殖实验结果显示,anti-IgM刺激时转基因小鼠的MZB细胞比FVB野生型小鼠对照增殖高2～5倍,但在LPS或PMA+ Ionomycin刺激时,两者差异无统计学意义.同时anti-IgM体内注射能诱导FVB小鼠的MZ B细胞凋亡,但转基因小鼠的MZ B细胞不发生凋亡.结论:BCL10表达水平与MALT淋巴瘤的前体细胞-MZ B细胞的增生具有正相关的量效关系,其导致增生的机制是其位于BCR受体下游使MZ B细胞在BCR受到刺激时增殖增强并且不发生凋亡.

Over-expressed BCL10 and mechanism of MALT lymphoma generation

OBJECTIVE: To understand the molecular mechanism of BCL10 over-expression on malignant phenotype of MALT lymphoma by using EμSR-BCL10 transgenic mice model.METHOD: Precursor of MALT lymphoma-marginal B cells were found highly expanded in EμSR-BCL10 transgenic mice.Signature markers for these cells were IgM+/CD21high/CD23low,and MZ B cells in transgenic mice were evaluated by staining of these three anti-bodies followed by flow cytometry analysis.Those cells were also isolated by CD43 microbeads followed by CD23 microbeads double negative selection,and proliferation assays were performed on these separated cells.In vivo anti-apoptotic effect to MZ B cells of over-expressed BCL10 were evaluated by injection of anti-IgM through tail vein.RESULTS: MZ B cell expanded in transgenic mice in a dose-dependent manner with BCL10 protein manner.Proliferation of MZ B cells from transgenic mice showed 2-5 times higher than those from FVB mice at the stimulation of anti-IgM,but no significant differences were observed on LPS and PMA+Ionomycin stimulation.Anti-IgM could induce apoptosis to MZ B cells of FVB mice but not transgenic mice in vivo.CONCLUSIONS: Over-expression of BCL10 causes MZ B cell expansion in a dose-dependent manner,which exerts proliferation-promoting and anti-apoptotic effects through BCR receptor pathway of marginal zone B cells.Our results may explain high-grade MLAT lymphoma malignant phenotypes.