A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression

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 arra...

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Main Authors: Rui Sun, Zhong Zheng, Li Wang, Shu Cheng, Qing Shi, Bin Qu, Di Fu, Christophe Leboeuf, Yan Zhao, Jing Ye, Anne Janin, Wei‐Li Zhao
Format: Article
Language:English
Published: Wiley 2021-01-01
Series:Molecular Oncology
Subjects:
Online Access:https://doi.org/10.1002/1878-0261.12834
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author Rui Sun
Zhong Zheng
Li Wang
Shu Cheng
Qing Shi
Bin Qu
Di Fu
Christophe Leboeuf
Yan Zhao
Jing Ye
Anne Janin
Wei‐Li Zhao
author_facet Rui Sun
Zhong Zheng
Li Wang
Shu Cheng
Qing Shi
Bin Qu
Di Fu
Christophe Leboeuf
Yan Zhao
Jing Ye
Anne Janin
Wei‐Li Zhao
author_sort Rui Sun
collection DOAJ
description 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.
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spelling doaj.art-beb4dab283e94096b22464de9a7d77952022-12-21T20:05:36ZengWileyMolecular Oncology1574-78911878-02612021-01-0115124626110.1002/1878-0261.12834A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progressionRui Sun0Zhong Zheng1Li Wang2Shu Cheng3Qing Shi4Bin Qu5Di Fu6Christophe Leboeuf7Yan Zhao8Jing Ye9Anne Janin10Wei‐Li Zhao11Shanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaDepartment of Laboratory Medicine Shanghai Rui Jin HospitalShanghai Jiao Tong University School of Medicine ChinaShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaU1165 Inserm/Université Paris 7Hôpital Saint Louis Paris FranceShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaLaboratory of Molecular Pathology Pôle de Recherches Sino‐Français en Science du Vivant et Génomique Shanghai ChinaU1165 Inserm/Université Paris 7Hôpital Saint Louis Paris FranceShanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ChinaMicroRNA (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.https://doi.org/10.1002/1878-0261.12834diffuse large B‐cell lymphomamicroRNAprognosisRas protein signal transductiontumor microenvironment
spellingShingle Rui Sun
Zhong Zheng
Li Wang
Shu Cheng
Qing Shi
Bin Qu
Di Fu
Christophe Leboeuf
Yan Zhao
Jing Ye
Anne Janin
Wei‐Li Zhao
A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
Molecular Oncology
diffuse large B‐cell lymphoma
microRNA
prognosis
Ras protein signal transduction
tumor microenvironment
title A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
title_full A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
title_fullStr A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
title_full_unstemmed A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
title_short A novel prognostic model based on four circulating miRNA in diffuse large B‐cell lymphoma: implications for the roles of MDSC and Th17 cells in lymphoma progression
title_sort novel prognostic model based on four circulating mirna in diffuse large b cell lymphoma implications for the roles of mdsc and th17 cells in lymphoma progression
topic diffuse large B‐cell lymphoma
microRNA
prognosis
Ras protein signal transduction
tumor microenvironment
url https://doi.org/10.1002/1878-0261.12834
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