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

• Published in: Experimental hematology 2016-04, Vol.44 (4), p.238-246.e2
• Main Authors: Marques, Sara Correia, Ranjbar, Benyamin, Laursen, Maria Bach, Falgreen, Steffen, Bilgrau, Anders Ellern, Bødker, Julie Støve, Jørgensen, Laura Krogh, Primo, Maria Nascimento, Schmitz, Alexander, Ettrup, Marianne Schmidt, Johnsen, Hans Erik, Bøgsted, Martin, Mikkelsen, Jacob Giehm, Dybkær, Karen
• Format: Article
• Language: English
• Subjects: Adult; Advanced Basic Science; Aged; Aged, 80 and over; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line, Tumor; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - genetics; Female; Forkhead Transcription Factors - genetics; Gene Expression; Gene Expression Profiling; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse - diagnosis; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - mortality; Male; MicroRNAs - genetics; Middle Aged; Prognosis; Repressor Proteins - genetics; Retrospective Studies; Transcriptome
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2015.12.007

The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) 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 patients with DLBCL, 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 had a prognostic impact using overall survival as outcome. With 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) revealed 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.