目的:B细胞淋巴瘤的特征是影响B细胞分化的多种遗传异常。为了扩大靶向治疗,深入掌握生发中心(GC)的分子动力学至关重要。转导蛋白β样1X连接受体1(TBL1XR1)和核受体共阻遏物1(NCOR1)在GC中起作用,调节多种致癌途径。它们在各种癌症中的预后作用已经确立,然而,它们对B细胞淋巴瘤的确切影响是难以捉摸的。
方法:对先前策划的188个B细胞淋巴瘤标本进行数字RNA定量(Nanostring),滤泡性淋巴瘤(FL),弥漫性大B细胞淋巴瘤,未指定(DLBCL-NOS),原发性睾丸淋巴瘤(PTL),浆细胞淋巴瘤(PBL),重新分析了TBL1XR1和NCOR1的表达,将它们与730个与遗传相关的基因并列。
结果:值得注意的是,TBL1XR1表达在PTL-ABC亚型与DLBCL-NOS-ABC亚型中显著升高(p<0.001),它们之间的GCB亚型没有明显差异。在FL中TBL1XR1的中位表达显著减少,然而,有趣的是,与FL相比,DLBCL-NOS的GCB亚型表达显着增强(p=0.001)。相比之下,NCOR1的表达轨迹在DLBCL-NOS中一致,PTL,PBL。在PBL中观察到TBL1XR1和NCOR1之间的强负相关(p=0.001)。重要的是,注意到TBL1XR1与几个DNA损伤修复(DDR)基因的明显关联,表明对DNA修复的影响。使用DLBCL-NOS的公共数据集进一步验证TBL1XR1-DDR基因签名。
结论:我们的探索性发现揭示了TBL1XR1/NCOR1在B细胞淋巴瘤变体中的表达模式。TBL1XR1-DDR基因连接提供了对潜在DNA修复作用的见解,为B细胞淋巴瘤的创新疗法铺路。
OBJECTIVE: B-cell lymphomas are characterized by diverse genetic anomalies affecting B-cell differentiation. To expand targeted therapies, an in-depth grasp of the molecular dynamics in the germinal center (GC) is vital. Transducin β-like 1 X-linked receptor 1 (
TBL1XR1) and nuclear receptor corepressor 1 (NCOR1) are instrumental within the GC, modulating myriad oncogenic pathways. Their prognostic roles in various cancers are established, yet their precise impact on B-cell lymphoma is elusive.
METHODS: Digital RNA quantification (Nanostring) of previously curated 188 B-cell lymphoma specimens across four subtypes, follicular lymphoma (FL), diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), primary testicular lymphoma (PTL), and plasmablastic lymphoma (PBL), was reanalyzed with focus on TBL1XR1 and NCOR1 expression, juxtaposing them with 730 ontogenically linked genes.
RESULTS: Notably, TBL1XR1 expression was significantly elevated in the PTL- ABC-subtype versus DLBCL-NOS- ABC-subtype (p<0.001), with no marked disparity in GCB-subtypes between them. The median TBL1XR1 expression was remarkably diminished in FL, yet, intriguingly, GCB-subtypes of DLBCL-NOS exhibited significantly enhanced expression compared to FL (p=0.001). In contrast, NCOR1\'s expression trajectory was consistent across DLBCL-NOS, PTL, and PBL. A strong inverse correlation between
TBL1XR1 and NCOR1 was observed in PBL (p=0.001). Importantly, TBL1XR1\'s pronounced association with several DNA Damage repair (DDR) genes was noted suggesting influence on DNA repair.
TBL1XR1-DDR gene signature was further validated employing a public data set of DLBCL-NOS.
CONCLUSIONS: Our exploratory findings unravel the expression patterns of
TBL1XR1/NCOR1 in B-cell lymphoma variants. The
TBL1XR1-DDR genes connection offers insights into potential DNA repair roles, paving avenues for innovative therapies in B-cell lymphomas.