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| Leukemia. 2015 May 14. pii: leu2015119. doi: 10.1038/leu.2015.119 |
| p53-dependent non-coding RNA networks in chronic lymphocytic leukemia. |
| Blume CJ1, Hotz-Wagenblatt A2, Hüllein J3, Sellner L4, Jethwa A5, Stolz T6, Slabicki M7, Lee K8, Sharathchandra A9, Benner A10, Dietrich S11, Oakes CC12, Dreger P13, Te Raa D14, Kater AP15, Jauch A16, Merkel O17, Oren M18, Hielscher T19, Zenz T20 |
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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.Leukemia advance online publication, 11 August 2015; doi:10.1038/leu.2015.119. |
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Publikations ID: 25971364 Quelle: öffnen |
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