MicroRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia

Aldo M. Roccaro, Antonio Sacco, Changzhong Chen, Judith Runnels, Xavier Leleu, Feda Azab, Abdel Kareem Azab, Xiaoying Jia, Hai T. Ngo, Molly R. Melhem, Nicholas Burwick, Lyuba Varticovski, Carl D. Novina, Barrett J. Rollins, Kenneth C. Anderson, Irene M. Ghobrial

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Multilevel genetic characterization of Waldenström macroglobulinemia (WM) is required to improve our understanding of the underlying molecular changes that lead to the initiation and progression of this disease. We performed microRNA-expression profiling of bone marrow-derived CD19+ WM cells, compared with their normal cellular counterparts and validated data by quantitative reversetranscription-polymerase chain reaction (qRT-PCR). We identified a WM-specific microRNA signature characterized by increased expression of microRNA-363*/-206/-494/-155/-184/-542-3p, and decreased expression of microRNA-9* (ANOVA;. P < .01). We found that microRNA-155 regulates proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways. Potential microRNA-155 target genes were identified using geneexpression profiling and included genes involved in cell-cycle progression, adhesion, and migration. Importantly, increased expression of the 6 miRNAs significantly correlated with a poorer outcome predicted by the International Prognostic Staging System for WM. We further demonstrated that therapeutic agents commonly used in WM alter the levels of the major miRNAs identified, by inducing downmodulation of 5 increased miRNAs and up-modulation of patient-downexpressed miRNA-9*. These data indicate that microRNAs play a pivotal role in the biology of WM; represent important prognostic marker; and provide the basis for the development of new microRNA-based targeted therapies in WM.

Original languageEnglish (US)
Pages (from-to)4391-4402
Number of pages12
JournalUnknown Journal
Volume113
Issue number18
DOIs
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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