LNA-mediated anti–miR-155 silencing in low-grade B-cell lymphomas

• Published in: Blood Vol. 120; no. 8; pp. 1678 - 1686
• Main Authors: Zhang, Yong, Roccaro, Aldo M., Rombaoa, Christopher, Flores, Ludmilla, Obad, Susanna, Fernandes, Stacey M., Sacco, Antonio, Liu, Yang, Ngo, Hai, Quang, Phong, Azab, Abdel Kareem, Azab, Feda, Maiso, Patricia, Reagan, Michaela, Brown, Jennifer R., Thai, To-Ha, Kauppinen, Sakari, Ghobrial, Irene M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 23.08.2012; Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Cell Proliferation; Female; Gene Silencing; Genetic Therapy; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - therapy; Medical sciences; Mice; Mice, Inbred BALB C; MicroRNAs - genetics; Oligonucleotides - genetics; Oligonucleotides - therapeutic use; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - therapeutic use; Tumor Cells, Cultured; Waldenstrom Macroglobulinemia - genetics; Waldenstrom Macroglobulinemia - pathology; Waldenstrom Macroglobulinemia - therapy; Gene silencing; Hematology; Lymphoproliferative syndrome; Malignant hemopathy; B-Lymphocyte; Lymphoma; Cancer; Low grade
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-02-410647

miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155–based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti–miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti–miR-155 delivered systemically showed uptake in the BM CD19+ cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155–knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti–miR-155–mediated inhibition of miR-155 in the treatment of WM.