TY - JOUR
T1 - High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma
AU - Marques, Sara Correia
AU - Ranjbar, Benyamin
AU - Laursen, Maria Bach
AU - Larsen, Steffen Falgreen
AU - Bilgrau, Anders Ellern
AU - Bødker, Julie Støve
AU - Jørgensen, Laura Theresa Krogh
AU - Primo, Maria Nascimento
AU - Schmitz, Alexander
AU - Ettrup, Marianne Schmidt
AU - Johnsen, Hans Erik
AU - Bøgsted, Martin
AU - Mikkelsen, Jacob Giehm
AU - Dybkær, Karen
N1 - Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1016/j.exphem.2015.12.007
DO - 10.1016/j.exphem.2015.12.007
M3 - Journal article
C2 - 26854484
SN - 0301-472X
VL - 44
SP - 238-246.e2
JO - Experimental Hematology
JF - Experimental Hematology
IS - 4
ER -