miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression
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Anja Seckinger1, Tobias Meißner1,2, Jérôme Moreaux3, Vladimir Benes4, Jens Hillengass1, Mirco Castoldi5, Jürgen Zimmermann4, Anthony D. Ho1, Anna Jauch6, Hartmut Goldschmidt1,7, Bernard Klein3, Dirk Hose1
1Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany
2Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, CA, USA
3Centre Hospitalier Universitaire Montpellier, Hôpital Saint-Eloi, Montpellier, France
4European Molecular Biology Laboratory, Heidelberg, Germany
5Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
6Institut für Humangenetik, Universität Heidelberg, Heidelberg, Germany
7Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany
Dirk Hose, e-mail: [email protected]
Keywords: miRNA, multiple myeloma, gene expression profiling, survival
Received: July 07, 2015 Accepted: September 30, 2015 Published: October 12, 2015
Purpose: microRNAs regulate gene-expression in biological and pathophysiological processes, including multiple myeloma. Here we address i) What are the number and magnitude of changes in miRNA-expression between normal plasma cells and myeloma- or MGUS-samples, and the latter two? ii) What is the biological relevance and how does miRNA-expression impact on gene-expression? iii) Is there a prognostic significance, and what is its background?
Experimental design: Ninety-two purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line-samples were investigated using miChip-arrays interrogating 559 human miRNAs. Impact on gene-expression was assessed by Affymetrix DNA-microarrays in two cohorts of myeloma patients (n = 677); chromosomal aberrations were assessed by iFISH, survival for 592 patients undergoing up-front high-dose chemotherapy.
Results: Compared to normal plasma cells, 67/559 miRNAs (12%) with fold changes of 4.6 to -3.1 are differentially expressed in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS and myeloma. Expression of miRNAs is associated with proliferation, chromosomal aberrations, tumor mass, and gene expression-based risk-scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free and overall survival, as do respective target-gene signatures.
Conclusions: The myeloma-miRNome confers a pattern of small changes of individual miRNAs impacting on gene-expression, biological functions, and survival.
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