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Leukemia. 2014 Jan;28(1):98-107. doi: 10.1038/leu.2013.246. Epub 2013 Aug 26.

Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia.

Author information

1
1] Department of Internal Medicine III, Ulm University, Ulm, Germany [2] Cooperation Unit 'Mechanisms of Leukemogenesis', German Cancer Research Center DKFZ, Heidelberg, Germany.
2
Department of Internal Medicine III, Ulm University, Ulm, Germany.
3
1] Department of Internal Medicine III, Ulm University, Ulm, Germany [2] Signalling to Chromatin Laboratory, Institute of Molecular Biology, Mainz, Germany.

Erratum in

  • Leukemia. 2014 Dec;28(12):2427. Zucknick, Manuela [Added].

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.

PMID:
23974981
DOI:
10.1038/leu.2013.246
[Indexed for MEDLINE]

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