High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma

Sara Correia Marques, Benyamin Ranjbar, Maria Bach Laursen, Steffen Falgreen Larsen, Anders Ellern Bilgrau, Julie Støve Bødker, Laura Theresa Krogh Jørgensen, Maria Nascimento Primo, Alexander Schmitz, Marianne Schmidt Ettrup, Hans Erik Johnsen, Martin Bøgsted, Jacob Giehm Mikkelsen, Karen Dybkær

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46 Citationer (Scopus)

Abstract

The standard treatment of diffuse large B-cell lymphoma (DLBCL) patients is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of DLBCL patients who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a showed prognostic impact using overall survival as outcome. Using risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B-cell-associated gene signatures (BAGS) showed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.

OriginalsprogEngelsk
TidsskriftExperimental Hematology
Vol/bind44
Udgave nummer4
Sider (fra-til)238-246.e2
Antal sider11
ISSN0301-472X
DOI
StatusUdgivet - 2016

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