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

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

doi:10.1016/j.exphem.2015.12.007

Cited by 54 publications

(42 citation statements)

References 42 publications

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“…These changes in expression are therefore potential prognostic biomarkers for use in clinical practice. It has been shown most recently using in vitro and in vivo studies that increased levels of miR-34a were observed in cell lines sensitive to doxorubicin, a drug in the R-CHOP regime, and this high expression had a prognostic impact on improved overall survival [61]. Downregulation of FOXP1 , a known target of miR-34a, could therefore potentially sensitise tumour cells to doxorubicin and improve efficacy of the drug in chemo-resistant patients.…”

Section: Functionally Significant Cellular Mirnas In Nhlmentioning

confidence: 99%

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

Bradshaw

Sutherland

Haupt

et al. 2016

Genes

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A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively. In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes. These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies. With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival.

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Section: Functionally Significant Cellular Mirnas In Nhlmentioning

confidence: 99%

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

Bradshaw

Sutherland

Haupt

et al. 2016

Genes

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“…Studies have highlighted the abnormal expression of miR‐34a in multiple solid malignancies and the role of miR‐34a as a tumor suppressor . The present study revealed that miR‐34a expression was impaired in KG‐1a cells and AML CD34 + CD38 − cells compared with normal CD34 + CD38 − cells.…”

Section: Discussionmentioning

confidence: 49%

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

et al. 2020

IUBMB Life

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We investigated the role of leukemia stem cells in chemoresistance and recurrence of acute myeloid leukemia. Total RNA was isolated from cells or tissues using TRIzol reagent. Cell viability was assessed with the tetrazolium assay. MicroRNA‐34a (miR‐34a), which acts on cell death regulation pathways, was noticeably downregulated in non‐M3 acute myeloid leukemia stem cells compared with normal hematopoietic stem cells. Furthermore, inhibition of miR‐34a‐mediated suppression in leukemia stem cells was associated with poor clinical outcomes and impaired treatment efficacy in acute myeloid leukemia. Transfection with a miR‐34a mimic triggered leukemia stem cell death and prevented leukemia. Bioinformatics analysis and a dual‐luciferase reporter assay showed that miR‐34a targeted the 3′‐untranslated region of histone deacetylase 2, and the reinforced expression of miR‐34a remarkably stimulated the expression of histone deacetylase 2 in leukemia stem cells. Ectopic miR‐34a expression triggered death of leukemia stem cells via pathways involving the Janus kinase 1‐signal transducer and activator of transcription 2‐p53 axis. Targeting leukemia stem cells to trigger cell death through upregulation of miR‐34a expression could be used to diagnose and treat acute myeloid leukemia.

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“…miRNA expression profiling was performed using GeneChip miRNA 1.0.2 arrays (Affymetrix, Santa Clara, CA) according to the manufacturer's protocol. The cell lines DB, FARAGE, OCI-Ly3, OCI-Ly7, OCI-Ly8, OCI-Ly19, NU-DHL-1, RIVA, and U2932 were prepared for hybridization using Flashtag HSR kit from Genesphere (Genesphere, Hatfield, PA) whereas HBL-1, MC-116, NU-DUL-1, SU-DHL-4, SU-DHL-5, and SU-DHL-8 were prepared using Fashtag Biotin HSR RNA labeling kit (Affymetrix) [14]. For GEP, RNA was labeled and hybridized to Affymetrix GeneChip Human Genome U133 (HG-U133) Plus 2.0 arrays, as described by the manufacturer.…”

Section: Global Mirna and Mrna Expression Profilingmentioning

confidence: 99%

“…Deregulation of miRNAs occurs early and consistently in tumor development and progression, and thus constitutes a promising source for discovery of novel biomarkers. Indeed, specific miRNAs and global miRNA expression profiles have shown significant potential as diagnostic as well as prognostic biomarkers for DLBCL [11][12][13], and several studies support their role in chemotherapy resistance [14][15][16]. Since DLBCL is a highly heterogeneous disease at the molecular level, we hypothesized that a panel of miRNAs associated to individual components of R-CHOP can improve robustness of individual markers and serve as a prognostic classifier predicting disease progression in DLBCL patients.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs associated to single drug components of R-CHOP identifies diffuse large B-cell lymphoma patients with poor outcome and adds prognostic value to the international prognostic index

et al. 2020

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Background: Treatment resistance is a major clinical challenge of diffuse large B-cell lymphoma (DLBCL) where approximately 40% of the patients have refractory disease or relapse. Since DLBCL is characterized by great clinical and molecular heterogeneity, the purpose of the present study was to investigate whether miRNAs associated to single drug components of R-CHOP can improve robustness of individual markers and serve as a prognostic classifier. Methods: Fifteen DLBCL cell lines were tested for sensitivity towards single drug compounds of the standard treatment R-CHOP: rituximab (R), cyclophosphamide (C), doxorubicin (H), and vincristine (O). For each drug, cell lines were ranked using the area under the dose-response curve and grouped as either sensitive, intermediate or resistant. Baseline miRNA expression data were obtained for each cell line in untreated condition, and differential miRNA expression analysis between sensitive and resistant cell lines identified 43 miRNAs associated to growth response after exposure towards single drugs of R-CHOP. Using the Affymetrix HG-U133 platform, expression levels of miRNA precursors were assessed in 701 diagnostic DLBCL biopsies, and miRNA-panel classifiers predicting disease progression were build using multiple Cox regression or random survival forest. Classifiers were validated and ranked by repeated cross-validation. Results: Prognostic accuracies were assessed by Brier Scores and time-varying area under the ROC curves, which revealed better performance of multivariate Cox models compared to random survival forest models. The Cox model including miR-146a, miR-155, miR-21, miR-34a, and miR-23a~miR-27a~miR-24-2 cluster performed the best and successfully stratified GCB-DLBCL patients into high-and low-risk of disease progression. In addition, combination of the Cox miRNA-panel and IPI substantially increased prognostic performance in GCB classified patients. Conclusion: As a proof of concept, we found that expression data of drug associated miRNAs display prognostic utility and adding these to IPI improves prognostic stratification of GCB-DLBCL patients treated with R-CHOP.

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

Cited by 54 publications

References 42 publications

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

MicroRNAs associated to single drug components of R-CHOP identifies diffuse large B-cell lymphoma patients with poor outcome and adds prognostic value to the international prognostic index

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