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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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Autores principales: Sun, Rui, Zheng, Zhong, Wang, Li, Cheng, Shu, Shi, Qing, Qu, Bin, Fu, Di, Leboeuf, Christophe, Zhao, Yan, Ye, Jing, Janin, Anne, Zhao, Wei‐Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782091/
https://www.ncbi.nlm.nih.gov/pubmed/33107145
http://dx.doi.org/10.1002/1878-0261.12834
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author Sun, Rui
Zheng, Zhong
Wang, Li
Cheng, Shu
Shi, Qing
Qu, Bin
Fu, Di
Leboeuf, Christophe
Zhao, Yan
Ye, Jing
Janin, Anne
Zhao, Wei‐Li
author_facet Sun, Rui
Zheng, Zhong
Wang, Li
Cheng, Shu
Shi, Qing
Qu, Bin
Fu, Di
Leboeuf, Christophe
Zhao, Yan
Ye, Jing
Janin, Anne
Zhao, Wei‐Li
author_sort Sun, Rui
collection PubMed
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 pubmed-77820912021-01-08 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 Sun, Rui Zheng, Zhong Wang, Li Cheng, Shu Shi, Qing Qu, Bin Fu, Di Leboeuf, Christophe Zhao, Yan Ye, Jing Janin, Anne Zhao, Wei‐Li Mol Oncol Research Articles 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. John Wiley and Sons Inc. 2020-11-09 2021-01 /pmc/articles/PMC7782091/ /pubmed/33107145 http://dx.doi.org/10.1002/1878-0261.12834 Text en © 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Sun, Rui
Zheng, Zhong
Wang, Li
Cheng, Shu
Shi, Qing
Qu, Bin
Fu, Di
Leboeuf, Christophe
Zhao, Yan
Ye, Jing
Janin, Anne
Zhao, Wei‐Li
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 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 Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782091/
https://www.ncbi.nlm.nih.gov/pubmed/33107145
http://dx.doi.org/10.1002/1878-0261.12834
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