Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
Laboratory of Molecular Pathology, Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Shanghai, China.
Mol Oncol. 2021 Jan;15(1):246-261. doi: 10.1002/1878-0261.12834. Epub 2020 Nov 9.
MicroRNA (miRNA) have been emerged as prognostic biomarkers in diffuse large B-cell lymphoma (DLBCL). To understand the potential underlying mechanisms and translate these findings into clinical prediction on lymphoma progression, large patient cohorts should be evaluated. Here, using miRNA PCR array, we analyzed the miRNA expression profiles in serum samples of 20 DLBCL patients at diagnosis, remission and relapse. Four candidate miRNA were identified and subsequently evaluated for their ability to predict relapse and survival. A prognostic model based on four circulating miRNA (miR21, miR130b, miR155 and miR28) was established and tested in a training cohort of 279 patients and in a validation cohort of 225 patients (NCT01852435). The prognostic value of the 4-circulating miRNA model was assessed by univariate and multivariate analyses. The novel 4-circulating miRNA prognostic model significantly predicted clinical outcome of DLBCL, independent of International Prognostic Index in the training cohort [hazard ratio (HR) = 2.83, 95% CI 2.14-3.51, P < 0.001] and in the validation cohort (HR = 2.71, 95% CI 1.91-3.50, P < 0.001). Moreover, DNA- and RNA-sequencing was performed on tumor samples to detect genetic mutations and signaling pathway dysregulation. DNA-sequencing data showed no significant difference of tumor mutation burden between the low-risk and the high-risk groups of the 4-circulating miRNA model. RNA-sequencing revealed a correlation between the 4-circulating miRNA model and aberrant Ras protein signaling transduction. The impact of the miRNA signature on oncogenic signaling and tumor microenvironment was analyzed in vitro and in vivo. In B-lymphoma cells, modulation of the miRNA regulated IGF1 and JUN expression, thereby altering MDSC and Th17 cells. In DLBCL patients, the high-risk group presented Ras signaling activation, increased MDSC and Th17 cells, and immunosuppressive status compared with the low-risk group. In conclusion, the easy-to-use 4-circulating miRNA prognostic model effectively predicted relapse and survival in DLBCL. Moreover, the tumor microenvironment contributes to the role of the 4-circulating miRNA model in DLBCL progression.
微小 RNA (miRNA) 已成为弥漫性大 B 细胞淋巴瘤 (DLBCL) 的预后生物标志物。为了了解潜在的机制并将这些发现转化为对淋巴瘤进展的临床预测，应该评估大量的患者队列。在这里，我们使用 miRNA PCR 阵列分析了 20 例 DLBCL 患者在诊断、缓解和复发时血清样本中的 miRNA 表达谱。鉴定出四个候选 miRNA，随后评估其预测复发和生存的能力。基于四个循环 miRNA (miR21、miR130b、miR155 和 miR28) 的预后模型在一个 279 例患者的训练队列和一个 225 例患者的验证队列中进行了建立和测试（NCT01852435）。通过单变量和多变量分析评估了 4 个循环 miRNA 模型的预后价值。在训练队列[风险比 (HR) = 2.83，95%CI 2.14-3.51，P < 0.001]和验证队列[风险比 (HR) = 2.71，95%CI 1.91-3.50，P < 0.001]中，新的 4 个循环 miRNA 预后模型显著预测了 DLBCL 的临床结局，独立于国际预后指数。此外，对肿瘤样本进行 DNA 和 RNA 测序以检测遗传突变和信号通路失调。DNA 测序数据显示，低风险组和高风险组之间肿瘤突变负担无显著差异循环 miRNA 模型。RNA 测序显示，4 个循环 miRNA 模型与异常 Ras 蛋白信号转导之间存在相关性。在体外和体内分析了 miRNA 特征对致癌信号和肿瘤微环境的影响。在 B 淋巴瘤细胞中，miRNA 的调节可调节 IGF1 和 JUN 的表达，从而改变 MDSC 和 Th17 细胞。在 DLBCL 患者中，与低风险组相比，高危组表现出 Ras 信号激活、增加的 MDSC 和 Th17 细胞以及免疫抑制状态。总之，易于使用的 4 个循环 miRNA 预后模型可有效预测 DLBCL 的复发和生存。此外，肿瘤微环境有助于 4 个循环 miRNA 模型在 DLBCL 进展中的作用。
