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Chronic Lymphocytic Leukemia

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

Leukemia volume 28, pages 98–107 (2014)Cite this article

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A Corrigendum to this article was published on 10 December 2014

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.

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Acknowledgements

We are thankful to the CLL patients and healthy probands for the generous donation of their primary tissue. We would also like to thank Stefan Fröhling and Claudia Scholl for their comments and to Doris Winter for her excellent technical support. This work was supported by the DKFZ intramural funding scheme (K109), by the Sander Foundation (no. 2010.036.1), by the Deutsche José Carreras Leukämie-Stiftung (R06/13v) and by the Deutsche Krebshilfe (Max-Eder Programme, no. 109321).

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  1. Department of Internal Medicine III, Ulm University, Ulm, Germany

    D Allegra, V Bilan, A Garding, H Döhner, S Stilgenbauer, F Kuchenbauer & D Mertens

  2. Cooperation Unit ‘Mechanisms of Leukemogenesis’, German Cancer Research Center DKFZ, Heidelberg, Germany

    D Allegra & D Mertens

  3. Signalling to Chromatin Laboratory, Institute of Molecular Biology, Mainz, Germany

    A Garding

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Allegra, D., Bilan, V., Garding, A. et al. Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. Leukemia 28, 98–107 (2014). https://doi.org/10.1038/leu.2013.246

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