title: Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia.
abstract: The MIR-15A/-16-1 tumor suppressor microRNAs (miRNAs) are deleted in leukemic cells from more than 50% of patients with chronic lymphocytic leukemia (CLL). As these miRNAs are also less abundant in patients without genomic deletion, their downregulation in CLL is likely to be caused by additional mechanisms. We found the primary transcripts (pri-miRNAs) of MIR-15a/-16/-15b to be elevated and processing intermediates (precursor miRNAs) to be reduced in cells from CLL patients (22/38) compared with non-malignant B-cells (n=14), indicating a block of miRNA maturation at the DROSHA processing step. Using a luciferase reporter assay for pri-miR processing we validated the defect in primary CLL cells. The block of miRNA maturation is restricted to specific miRNAs and can be found in the cell line MEC-2, but not in MEC-1, even though both are derived from the same CLL patient. In these cells, the RNA-specific deaminase ADARB1 leads to reduced pri-miRNA processing, but full processing efficiency is recovered upon deletion of the RNA-binding domains or nuclear localization of ADARB1. Thus, we show that, apart from genomic deletion or transcriptional downregulation, aberrant processing of miRNA leads to specific reduction of miRNAs in leukemic cells. This represents a novel oncogenic mechanism in the pathogenesis of CLL.
authors: 1] Department of Internal Medicine III, Ulm University, Ulm, Germany [2] Cooperation Unit 'Mechanisms of Leukemogenesis', German Cancer Research Center DKFZ, Heidelberg, Germany.
authors: D
authors: D
authors: Allegra
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: V
authors: V
authors: Bilan
authors: 1] Department of Internal Medicine III, Ulm University, Ulm, Germany [2] Signalling to Chromatin Laboratory, Institute of Molecular Biology, Mainz, Germany.
authors: A
authors: A
authors: Garding
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: H
authors: H
authors: Döhner
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: S
authors: S
authors: Stilgenbauer
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: F
authors: F
authors: Kuchenbauer
authors: 1] Department of Internal Medicine III, Ulm University, Ulm, Germany [2] Cooperation Unit 'Mechanisms of Leukemogenesis', German Cancer Research Center DKFZ, Heidelberg, Germany.
authors: D
authors: D
authors: Mertens
authors: M
authors: M
authors: Zucknick
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins; D043244:Ribonuclease III / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; D051176:beta Catenin; C517918:DROSHA protein, human; D043244:Ribonuclease III; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
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