MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma
| Autor: | Maria Nascimento Primo, Emil Aagaard Thomsen, Xiaohong Tan, Ditte Starberg Jespersen, Anna Amanda Schönherz, Laura Barrett Ryø, Hanne Due, Martin Bøgsted, Karen Dybkær, Jacob Giehm Mikkelsen, Yuyang Pang, Anne Stidholt Roug, Ken H. Young, Min Xiao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncology Cell Cycle Proteins THERAPY 0302 clinical medicine International Prognostic Index immune system diseases hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols Lymphoid Neoplasia Hematology Middle Aged Protein-Tyrosine Kinases Prognosis MIR-155 Treatment Outcome Vincristine R-CHOP 030220 oncology & carcinogenesis SPINDLE-ASSEMBLY CHECKPOINT Rituximab Lymphoma Large B-Cell Diffuse medicine.drug medicine.medical_specialty DOXORUBICIN Cyclophosphamide CLASSIFICATION Cell Line 03 medical and health sciences Internal medicine microRNA medicine Humans WEE1 SIGNATURES SUPPRESSION PI3K/AKT business.industry Oncomir Germinal Center medicine.disease Lymphoma MicroRNAs 030104 developmental biology Doxorubicin Prednisone business Diffuse large B-cell lymphoma |
| Zdroj: | Due, H, Schönherz, A A, Ryø, L, Primo, M N, Jespersen, D S, Thomsen, E A, Roug, A S, Xiao, M, Tan, X, Pang, Y, Young, K H, Bøgsted, M, Mikkelsen, J G & Dybkær, K 2019, ' MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma ', Blood advances, vol. 3, no. 7, pp. 1185-1196 . https://doi.org/10.1182/bloodadvances.2018029660 Due, H, Schönherz, A A, Ryø, L, Primo, M N, Jespersen, D S, Thomsen, E A, Roug, A S, Xiao, M, Tan, X, Pang, Y, Young, K H, Bøgsted, M, Mikkelsen, J G & Dybkær, K 2019, ' MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma ', Blood Advances, vol. 3, no. 7, pp. 1185-1196 . https://doi.org/10.1182/bloodadvances.2018029660 |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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