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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Due, H; Schönherz, AA; Ryø, L; Primo, MN; Jespersen, DS; Thomsen, EA; Roug, AS; Xiao, M; Tan, X; Pang, Y; Young, KH; Bøgsted, M; Mikkelsen, JG; Dybkær, K

Published Date

  • April 9, 2019

Published In

  • Blood Adv

Volume / Issue

  • 3 / 7

Start / End Page

  • 1185 - 1196

PubMed ID

  • 30967394

Pubmed Central ID

  • PMC6457225

Electronic International Standard Serial Number (EISSN)

  • 2473-9537

Digital Object Identifier (DOI)

  • 10.1182/bloodadvances.2018029660

Language

  • eng

Conference Location

  • United States