1. The DLEU2/miR-15a/16-1 Cluster Controls B Cell Proliferation and Its Deletion Leads to Chronic Lymphocytic Leukemia
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Rachael Siegel, Anna Migliazza, Marta Crespo, Riccardo Dalla-Favera, Andrea Califano, Qiong Shen, Govind Bhagat, Marie Lia, Tongwei Mo, Ulf Klein, and Alberto Ambesi-Impiombato
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Cancer Research ,Chronic lymphocytic leukemia ,HUMDISEASE ,Lymphoproliferative disorders ,Mice, Transgenic ,CELLCYCLE ,Biology ,Pathogenesis ,Mice ,Transferases ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cell Proliferation ,Regulation of gene expression ,B-Lymphocytes ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,Proteins ,Cell Biology ,Cell cycle ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Blotting, Southern ,MicroRNAs ,Oncology ,Gene Expression Regulation ,Multigene Family ,Chromosomal region ,Immunology ,Cancer research ,Monoclonal B-cell lymphocytosis ,RNA ,Gene Deletion - Abstract
SummaryChronic lymphocytic leukemia (CLL) is a malignancy of B cells of unknown etiology. Deletions of the chromosomal region 13q14 are commonly associated with CLL, with monoclonal B cell lymphocytosis (MBL), which occasionally precedes CLL, and with aggressive lymphoma, suggesting that this region contains a tumor-suppressor gene. Here, we demonstrate that deletion in mice of the 13q14-minimal deleted region (MDR), which encodes the DLEU2/miR-15a/16-1 cluster, causes development of indolent B cell-autonomous, clonal lymphoproliferative disorders, recapitulating the spectrum of CLL-associated phenotypes observed in humans. miR-15a/16-1-deletion accelerates the proliferation of both human and mouse B cells by modulating the expression of genes controlling cell-cycle progression. These results define the role of 13q14 deletions in the pathogenesis of CLL.
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