MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12885-90. doi: 10.1073/pnas.0806202105. Epub 2008 Aug 26.


Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b approximately 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 approximately 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 approximately 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b approximately 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Base Sequence
  • Bcl-2-Like Protein 11
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, Neoplasm*
  • Health
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Monoclonal Gammopathy of Undetermined Significance
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology*
  • Plasma Cells / metabolism
  • Plasma Cells / pathology
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Interleukin-6 / metabolism
  • Repressor Proteins / metabolism
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • p300-CBP Transcription Factors / metabolism


  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins
  • Receptors, Interleukin-6
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Tumor Suppressor Protein p53
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor