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

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  • Hanne Due, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
  • ,
  • Anna Amanda Schönherz
  • Laura Ryø
  • Maria Nascimento Primo
  • ,
  • Ditte Starberg Jespersen, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
  • ,
  • Emil Aagaard Thomsen
  • Anne Stidholt Roug
  • Min Xiao, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
  • ,
  • Xiaohong Tan, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
  • ,
  • Yuyang Pang, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
  • ,
  • Ken H Young, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
  • ,
  • Martin Bøgsted
  • Jacob Giehm Mikkelsen
  • Karen Dybkær, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Department of Nuclear Medicine and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark.

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.

OriginalsprogEngelsk
TidsskriftBlood Advances
Vol/bind3
Nummer7
Sider (fra-til)1185-1196
Antal sider12
ISSN2473-9529
DOI
StatusUdgivet - 9 apr. 2019

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© 2019 by The American Society of Hematology.

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