title: miRNAs in multiple myeloma--a survival relevant complex regulator of gene expression.
abstract: OBJECTIVE
  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?
  
  
  METHODS
  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.
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Seckinger
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, CA, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meißner
authors.affiliation: Centre Hospitalier Universitaire Montpellier, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Moreaux
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.affiliation: Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Castoldi
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Institut für Humangenetik, Universität Heidelberg, Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Centre Hospitalier Universitaire Montpellier, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010950:Plasma Cells / Q000502:physiology; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D035683:MicroRNAs
keywords: gene expression profiling; miRNA; multiple myeloma; survival