İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir 35340, Türkiye.
Basic and Translational Research Program, İzmir Biomedicine and Genome Center, İzmir 35340, Türkiye.
Cells. 2022 Oct 27;11(21):3394. doi: 10.3390/cells11213394.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8 T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8 T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8 T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.
套细胞淋巴瘤（MCL）是一种侵袭性 B 细胞非霍奇金淋巴瘤（NHL）亚型，其特征是 CCND1 和 SOX11 基因的过度表达。尽管最近在治疗方法上有所改进，但它通常与临床预后不良相关。与 MCL 发生和预后相关的基因在很大程度上仍然未知。通过全转录组测序（WTS），我们鉴定了与反应性扁桃体 B 细胞亚群相比在 MCL 病例中差异表达的 mRNAs、lncRNAs 和替代转录本。CCND1、VCAM1 和 VWF mRNAs 以及 MIR100HG 和 ROR1-AS1 lncRNAs 是前 10 个表达最显著上调、与致癌相关的转录本之一。对每个上调转录本的生存分析表明，MCL 病例中 VWF mRNA 高表达和 FTX lncRNA 低表达与总生存不良相关。同样，高度表达过表达的替代转录本 MSTRG.153013.3 与 MCL 生存缩短相关。MCL 病例中明显下调了已知的肿瘤抑制候选基因（如 PI3KIP1、UBXN）。差异表达的蛋白编码基因在与侵袭和转移相关的信号通路中富集。基于 CIBERSORTx 估计的肿瘤浸润免疫细胞丰度的生存分析表明，CD8 T 细胞或静止 NK 细胞的高比例和嗜酸性粒细胞的低比例与诊断性 MCL 病例的总生存不良相关。肿瘤浸润 CD8 T 细胞丰度和过表达的致癌基因候选物的综合分析表明，MCL 病例中 CD8 T 细胞比例高、FTX 或 PCA3 表达低的患者可能具有高危 MCL。WTS 结果通过选定转录本的 qRT-PCR 以及线性相关分析进行了交叉验证。总之，MCL 肿瘤中与致癌相关的转录本的表达水平和/或微环境免疫细胞的比例可用于改善预后，从而改善患者管理和结局。
