title: Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia.
abstract: This study was conducted to investigate the possibility that TP53 mRNA is variably expressed in chronic lymphocytic leukaemia (CLL) and that under-expression is associated with TP53 dysfunction and adverse outcome. Although TP53 mRNA levels did indeed vary among the 104 CLL samples examined, this variability resulted primarily from over-expression of TP53 mRNA in 18 samples, all of which lacked TP53 deletion/mutation. These patients had higher lymphocyte counts and shorter overall and treatment-free survival times compared to cases with low TP53 mRNA expression and no TP53 deletion/mutation. Furthermore, TP53 mRNA levels did not correlate with levels of TP53 protein or its transcriptional target CDKN1A. We speculated that the adverse outcome associated with TP53 mRNA over-expression might reflect variation in levels of MIR15A and MIR16-1, which are encoded on chromosome 13q14 and target TP53 and some oncogenes including BCL2. In keeping with our hypothesis, 13q14 copy number and levels of MIR15A/MIR16-1 correlated positively with one another but negatively with levels of TP53 mRNA and BCL2 mRNA. Our findings support a model in which loss of MIR15A/MIR16-1 at chromosome 13q14 results in adverse outcome due to de-repression of oncogenes such as BCL2, and up-regulation of TP53 mRNA as a bystander effect.
authors.affiliation: Department of Haematology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Mosavar
authors.initials: M
authors.lastname: Farahani
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Gillian G
authors.initials: GG
authors.lastname: Johnson
authors.forename: Melanie
authors.initials: M
authors.lastname: Oates
authors.forename: Mark
authors.initials: M
authors.lastname: Atherton
authors.forename: Angela
authors.initials: A
authors.lastname: Douglas
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kalakonda
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
mesh_terms: D000368:Aged; D002851:Chromatography, High Pressure Liquid; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: 13q14; BCL2; CLL; MIR15A/16-1; TP53