MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Flavia Pichiorri, Sung Suk Suh, Marco Ladetto, Michael Kuehl, Tiziana Palumbo, Daniela Drandi, Cristian Taccioli, Nicola Zanesi, Hansjuerg Alder, John P. Hagan, Reinhold Munker, Stefano Volinia, Mario Boccadoro, Ramiro Garzon, Antonio Palumbo, Rami I. Aqeilan, Carlo M. Croce

Research output: Contribution to journalArticlepeer-review

495 Scopus citations

Abstract

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∼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∼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∼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∼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.

Original languageAmerican English
Pages (from-to)12885-12890
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number35
DOIs
StatePublished - 2 Sep 2008

Keywords

  • MGUS
  • PCAF
  • Plasma cells
  • SOCS-1
  • Tumor suppressor gene

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