title: p53-dependent non-coding RNA networks in chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Blume
authors.affiliation: Core Facility Genomics and Proteomics, Bioinformatics Group, DKFZ, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hotz-Wagenblatt
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Sellner
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jethwa
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Stolz
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Slabicki
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Sharathchandra
authors.affiliation: Division of Biostatistics, DKFZ, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
authors.forename: C C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Dreger
authors.affiliation: Department of Haematology, Academic Medical Centre, Amsterdam, The Netherlands.|Laboratory of Experimental Immunology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: te Raa
authors.affiliation: Department of Haematology, Academic Medical Centre, Amsterdam, The Netherlands.|Laboratory of Experimental Immunology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Kater
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Oren
authors.affiliation: Division of Biostatistics, DKFZ, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Zenz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C577276:NEAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53