Oncotarget

Research Papers:

miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression

Anja Seckinger _, Tobias Meißner, Jérôme Moreaux, Vladimir Benes, Jens Hillengass, Mirco Castoldi, Jürgen Zimmermann, Anthony D. Ho, Anna Jauch, Hartmut Goldschmidt, Bernard Klein and Dirk Hose

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Oncotarget. 2015; 6:39165-39183. https://doi.org/10.18632/oncotarget.5381

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Abstract

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

Correspondence to:

Dirk Hose, e-mail: dirk.hose@med.uni-heidelberg.de

Keywords: miRNA, multiple myeloma, gene expression profiling, survival

Received: July 07, 2015     Accepted: September 30, 2015     Published: October 12, 2015

ABSTRACT

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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