Loss ofMIR15AandMIR16-1at 13q14 is associated with increasedTP53mRNA, de-repression ofBCL2and adverse outcome in chronic lymphocytic leukaemia
- 18 July 2014
- journal article
- Published by Wiley in British Journal of Haematology
- Vol. 167 (3), 346-355
- https://doi.org/10.1111/bjh.13043
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.This publication has 42 references indexed in Scilit:
- Eμ/miR-125b transgenic mice develop lethal B-cell malignanciesLeukemia, 2011
- 13q14 Deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemiaGenes, Chromosomes and Cancer, 2011
- Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia: cytogenetic, FISH and clinical studiesEuropean Journal of Haematology, 2008
- Imperfect correlation between p53 dysfunction and deletion of TP53 and ATM in chronic lymphocytic leukaemiaLeukemia, 2006
- miR-15 and miR-16 induce apoptosis by targeting BCL2Proceedings of the National Academy of Sciences of the United States of America, 2005
- Chronic Lymphocytic LeukemiaThe New England Journal of Medicine, 2005
- Regulation of p53 activity through lysine methylationNature, 2004
- Detection of p53 dysfunction by flow cytometry in chronic lymphocytic leukaemiaBritish Journal of Haematology, 2004
- The functions of animal microRNAsNature, 2004
- Genomic Aberrations and Survival in Chronic Lymphocytic LeukemiaThe New England Journal of Medicine, 2000