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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 22, 2008; DOI 10.1182/blood-2008-09-178228.
LYMPHOID NEOPLASIA microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia1 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2 Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy; 3 Unit of Blood Diseases and Cell Therapies, University of Brescia Medical School, Brescia, Italy; 4 Center for Cancer Research, National Cancer Institute, Bethesda, MD; and 5 Cancer Immunology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
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 reverse-transcription–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-
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B 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 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. 
