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MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma

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MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. / Due, Hanne; Schönherz, Anna Amanda; Ryø, Laura; Primo, Maria Nascimento; Jespersen, Ditte Starberg; Thomsen, Emil Aagaard; Roug, Anne Stidholt; Xiao, Min; Tan, Xiaohong; Pang, Yuyang; Young, Ken H; Bøgsted, Martin; Mikkelsen, Jacob Giehm; Dybkær, Karen.

In: Blood Advances, Vol. 3, No. 7, 09.04.2019, p. 1185-1196.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Author

Due, Hanne ; Schönherz, Anna Amanda ; Ryø, Laura ; Primo, Maria Nascimento ; Jespersen, Ditte Starberg ; Thomsen, Emil Aagaard ; Roug, Anne Stidholt ; Xiao, Min ; Tan, Xiaohong ; Pang, Yuyang ; Young, Ken H ; Bøgsted, Martin ; Mikkelsen, Jacob Giehm ; Dybkær, Karen. / MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. In: Blood Advances. 2019 ; Vol. 3, No. 7. pp. 1185-1196.

Bibtex

@article{d11c73e4df5e402cac13b9270b892909,
title = "MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma",
abstract = "A major clinical challenge of diffuse large B-cell lymphoma (DLBCL) is that up to 40% of patients have refractory disease or relapse after initial response to therapy as a result of drug-specific molecular resistance. The purpose of the present study was to investigate microRNA (miRNA) involvement in vincristine resistance in DLBCL, which was pursued by functional in vitro analysis in DLBCL cell lines and by outcome analysis of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Differential miRNA expression analysis identified miR-155 as highly expressed in vincristine-sensitive DLBCL cell lines compared with resistant ones. Ectopic upregulation of miR-155 sensitized germinal-center B-cell-like (GCB)-DLBCL cell lines to vincristine, and consistently, reduction and knockout of miR-155 induced vincristine resistance, documenting that miR-155 functionally induces vincristine sensitivity. Target gene analysis identified miR-155 as inversely correlated with Wee1, supporting Wee1 as a target of miR-155 in DLBCL. Chemical inhibition of Wee1 sensitized GCB cells to vincristine, suggesting that miR-155 controls vincristine response through Wee1. Outcome analysis in clinical cohorts of DLBCL revealed that high miR-155 expression level was significantly associated with superior survival for R-CHOP-treated patients of the GCB subclass, independent of international prognostic index, challenging the commonly accepted perception of miR-155 as an oncomiR. However, miR-155 did not provide prognostic information when analyzing the entire DLBCL cohort or activated B-cell-like classified patients. In conclusion, we experimentally confirmed a direct link between high miR-155 expression and vincristine sensitivity in DLBCL and documented an improved clinical outcome of GCB-classified patients with high miR-155 expression level.",
keywords = "CLASSIFICATION, DOXORUBICIN, MIR-155, PI3K/AKT, R-CHOP, SIGNATURES, SPINDLE-ASSEMBLY CHECKPOINT, SUPPRESSION, THERAPY, WEE1",
author = "Hanne Due and Sch{\"o}nherz, {Anna Amanda} and Laura Ry{\o} and Primo, {Maria Nascimento} and Jespersen, {Ditte Starberg} and Thomsen, {Emil Aagaard} and Roug, {Anne Stidholt} and Min Xiao and Xiaohong Tan and Yuyang Pang and Young, {Ken H} and Martin B{\o}gsted and Mikkelsen, {Jacob Giehm} and Karen Dybk{\ae}r",
note = "Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = apr,
day = "9",
doi = "10.1182/bloodadvances.2018029660",
language = "English",
volume = "3",
pages = "1185--1196",
journal = "Blood advances",
issn = "2473-9529",
publisher = "ASH Publications",
number = "7",

}

RIS

TY - JOUR

T1 - MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma

AU - Due, Hanne

AU - Schönherz, Anna Amanda

AU - Ryø, Laura

AU - Primo, Maria Nascimento

AU - Jespersen, Ditte Starberg

AU - Thomsen, Emil Aagaard

AU - Roug, Anne Stidholt

AU - Xiao, Min

AU - Tan, Xiaohong

AU - Pang, Yuyang

AU - Young, Ken H

AU - Bøgsted, Martin

AU - Mikkelsen, Jacob Giehm

AU - Dybkær, Karen

N1 - Publisher Copyright: © 2019 by The American Society of Hematology. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/4/9

Y1 - 2019/4/9

N2 - A major clinical challenge of diffuse large B-cell lymphoma (DLBCL) is that up to 40% of patients have refractory disease or relapse after initial response to therapy as a result of drug-specific molecular resistance. The purpose of the present study was to investigate microRNA (miRNA) involvement in vincristine resistance in DLBCL, which was pursued by functional in vitro analysis in DLBCL cell lines and by outcome analysis of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Differential miRNA expression analysis identified miR-155 as highly expressed in vincristine-sensitive DLBCL cell lines compared with resistant ones. Ectopic upregulation of miR-155 sensitized germinal-center B-cell-like (GCB)-DLBCL cell lines to vincristine, and consistently, reduction and knockout of miR-155 induced vincristine resistance, documenting that miR-155 functionally induces vincristine sensitivity. Target gene analysis identified miR-155 as inversely correlated with Wee1, supporting Wee1 as a target of miR-155 in DLBCL. Chemical inhibition of Wee1 sensitized GCB cells to vincristine, suggesting that miR-155 controls vincristine response through Wee1. Outcome analysis in clinical cohorts of DLBCL revealed that high miR-155 expression level was significantly associated with superior survival for R-CHOP-treated patients of the GCB subclass, independent of international prognostic index, challenging the commonly accepted perception of miR-155 as an oncomiR. However, miR-155 did not provide prognostic information when analyzing the entire DLBCL cohort or activated B-cell-like classified patients. In conclusion, we experimentally confirmed a direct link between high miR-155 expression and vincristine sensitivity in DLBCL and documented an improved clinical outcome of GCB-classified patients with high miR-155 expression level.

AB - A major clinical challenge of diffuse large B-cell lymphoma (DLBCL) is that up to 40% of patients have refractory disease or relapse after initial response to therapy as a result of drug-specific molecular resistance. The purpose of the present study was to investigate microRNA (miRNA) involvement in vincristine resistance in DLBCL, which was pursued by functional in vitro analysis in DLBCL cell lines and by outcome analysis of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Differential miRNA expression analysis identified miR-155 as highly expressed in vincristine-sensitive DLBCL cell lines compared with resistant ones. Ectopic upregulation of miR-155 sensitized germinal-center B-cell-like (GCB)-DLBCL cell lines to vincristine, and consistently, reduction and knockout of miR-155 induced vincristine resistance, documenting that miR-155 functionally induces vincristine sensitivity. Target gene analysis identified miR-155 as inversely correlated with Wee1, supporting Wee1 as a target of miR-155 in DLBCL. Chemical inhibition of Wee1 sensitized GCB cells to vincristine, suggesting that miR-155 controls vincristine response through Wee1. Outcome analysis in clinical cohorts of DLBCL revealed that high miR-155 expression level was significantly associated with superior survival for R-CHOP-treated patients of the GCB subclass, independent of international prognostic index, challenging the commonly accepted perception of miR-155 as an oncomiR. However, miR-155 did not provide prognostic information when analyzing the entire DLBCL cohort or activated B-cell-like classified patients. In conclusion, we experimentally confirmed a direct link between high miR-155 expression and vincristine sensitivity in DLBCL and documented an improved clinical outcome of GCB-classified patients with high miR-155 expression level.

KW - CLASSIFICATION

KW - DOXORUBICIN

KW - MIR-155

KW - PI3K/AKT

KW - R-CHOP

KW - SIGNATURES

KW - SPINDLE-ASSEMBLY CHECKPOINT

KW - SUPPRESSION

KW - THERAPY

KW - WEE1

U2 - 10.1182/bloodadvances.2018029660

DO - 10.1182/bloodadvances.2018029660

M3 - Journal article

C2 - 30967394

VL - 3

SP - 1185

EP - 1196

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 7

ER -