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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4391-4402.
Prepublished online as a Blood First Edition Paper on December 12, 2008December 22, 2008; DOI 10.1182/blood-2008-09-178228.
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Submitted September 9, 2008
Accepted November 15, 2008
microRNA expression in the biology, prognosis and therapy of Waldenstrom 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, and Irene M Ghobrial*
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
Cancer Immunology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
* Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu.
Multi-level genetic characterization of Waldenstrom 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 to their normal cellular counterparts and validated data by 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< 0.01).
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-kB pathways. Potential microRNA-155 target genes were identified using gene-expression-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 (rituximab/perifosine/bortezomib) alter the levels of the major miRNAs identified, by inducing down-modulation of five increased miRNAs (all but miR-206) 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.
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