NOTCH1基因突变促进复发难治型弥漫大B淋巴瘤增殖及转移的机制研究

The clinical treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) remains challenging. Recent study suggested DLBCL patients with NTOCH1 mutations (N1 subtype) might have a poor prognosis. However, the pathogenic mechanism of NOTCH1 mutation is still unclear. Our next generation sequencing data demonstrated that NOTCH1 mutations occurred in DLBCL tumor tissue. We further confirmed that mutations in NOTCH1 increased the expression of its mRNA and protein, and NOTCH1 down-regulation in DLBCL cell could decrease cell proliferation and prevent cell invasion and migration. So, we hypothesized that NOTHC1 mutations changed the stability of mRNA and protein, which lead to abnormally increase the expression and activate downstream Notch signaling pathway. Based on these findings, we prepared to clarify the multiple mechanisms between NOTCH1 gene mutation and cell proliferation and metastasis in R/R DLBCL. Moreover, the effective and safety of NOTCH1 inhibitor as a therapeutic target will be explored through in vivo and in vitro experiments, which could provide more clues for individualized therapy of N1 subtype in DLBCL patients.

复发难治型弥漫大B细胞淋巴瘤（R/R DLBCL）是临床的治疗难点。最新研究将DLBCL进行遗传学亚型分类，携带NOTCH1突变定义为临床预后较差的N1型，但其相关分子机制尚不明确。本课题组前期二代测序结果发现R/R DLBCL患者肿瘤组织存在NOTCH1基因突变，且突变后mRNA及蛋白表达均增加；初步表型分析显示NOTCH1表达下调后肿瘤细胞增殖及转移能力减弱。因此推测，NOTCH1基因突变后mRNA或蛋白稳定性改变导致其表达异常增加，进而激活下游Notch信号通路使肿瘤细胞持续增殖并发生转移。鉴于此，本课题拟深入研究R/R DLBCL肿瘤组织中NOTCH1基因突变与肿瘤细胞恶性增殖及转移的作用机制，进而通过体内外实验探讨NOTCH1作为R/R DLBCL治疗靶标的有效性，以期为N1型患者个体化靶向治疗研究提供实验线索。

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