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Chronic lymphocytic leukemia

p53-dependent non-coding RNA networks in chronic lymphocytic leukemia

Leukemia volume 29, pages 2015–2023 (2015)Cite this article

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Abstract

Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent microRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent microRNAs (miRNAs; miR-182-5p, miR-7-5p and miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and long intergenic non-coding RNA p21 (lincRNA-p21) are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 are closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.

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Acknowledgements

This study was supported by research grants of the German Cancer Aid, GIF and the MDACC DKFZ SINF program. We thank the European Research Initiative on CLL (ERIC) for providing patient samples, HJ Delecluse and M Rogers for providing cell lines and the DKFZ Genomics and Proteomics facility for sequencing services.

Author Contributions

CJB designed and performed research, analyzed data and wrote the paper; TH and AH-W analyzed data; JH and AJ designed and performed research and analyzed data; TS, KL and SCA performed research; CCO provided IGHV mutation data; AJ provided FISH data; LS, MS, AB, AH, SD, PD, MO and OM contributed to data interpretation; DR, SD, LS, PD, TZ and AK provided patient samples; TZ designed research, interpreted data and wrote the paper.

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Authors and Affiliations

  1. Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    C J Blume, J Hüllein, L Sellner, A Jethwa, T Stolz, M Slabicki, K Lee, S Dietrich, O Merkel & T Zenz

  2. Core Facility Genomics and Proteomics, Bioinformatics Group, DKFZ, Heidelberg, Germany

    A Hotz-Wagenblatt

  3. Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    L Sellner, S Dietrich, P Dreger & T Zenz

  4. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    A Sharathchandra & M Oren

  5. Division of Biostatistics, DKFZ, Heidelberg, Germany

    A Benner & T Hielscher

  6. Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany

    C C Oakes

  7. Department of Haematology, Academic Medical Centre, Amsterdam, The Netherlands

    D te Raa & A P Kater

  8. Laboratory of Experimental Immunology, Academic Medical Centre, Amsterdam, The Netherlands

    D te Raa & A P Kater

  9. Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany

    A Jauch

  10. Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria

    O Merkel

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  1. C J Blume
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  2. A Hotz-Wagenblatt
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Correspondence to T Zenz.

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Blume, C., Hotz-Wagenblatt, A., Hüllein, J. et al. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia. Leukemia 29, 2015–2023 (2015). https://doi.org/10.1038/leu.2015.119

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