MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line
Cyclophosphamide
/ therapeutic use
Doxorubicin
/ therapeutic use
Germinal Center
/ pathology
Humans
Lymphoma, Large B-Cell, Diffuse
/ diagnosis
MicroRNAs
/ metabolism
Middle Aged
Prednisone
/ therapeutic use
Prognosis
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Rituximab
/ therapeutic use
Treatment Outcome
Vincristine
/ agonists
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
09 04 2019
09 04 2019
Historique:
received:
10
12
2018
accepted:
04
03
2019
entrez:
11
4
2019
pubmed:
11
4
2019
medline:
24
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30967394
pii: bloodadvances.2018029660
doi: 10.1182/bloodadvances.2018029660
pmc: PMC6457225
doi:
Substances chimiques
Cell Cycle Proteins
0
MIRN155 microRNA, human
0
MicroRNAs
0
R-CHOP protocol
0
Rituximab
4F4X42SYQ6
Vincristine
5J49Q6B70F
Doxorubicin
80168379AG
Cyclophosphamide
8N3DW7272P
Protein-Tyrosine Kinases
EC 2.7.10.1
WEE1 protein, human
EC 2.7.10.2
Prednisone
VB0R961HZT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1185-1196Informations de copyright
© 2019 by The American Society of Hematology.
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