Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
Language English Country United States Media print-electronic
Document type Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
PubMed
30447004
DOI
10.1002/ijc.31999
Knihovny.cz E-resources
- Keywords
- CLL, DNA methylation, TP63, gene expression, stereotypy,
- MeSH
- Apoptosis genetics MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell blood genetics pathology MeSH
- Epigenomics methods MeSH
- Humans MeSH
- RNA, Small Interfering metabolism MeSH
- DNA Methylation genetics MeSH
- Tumor Cells, Cultured MeSH
- Tumor Suppressor Proteins genetics metabolism MeSH
- Primary Cell Culture MeSH
- Promoter Regions, Genetic genetics MeSH
- Receptors, Antigen, B-Cell metabolism MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Sequence Analysis, RNA MeSH
- Gene Expression Profiling methods MeSH
- Transcription Factors genetics metabolism MeSH
- Up-Regulation MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- RNA, Small Interfering MeSH
- Tumor Suppressor Proteins MeSH
- Receptors, Antigen, B-Cell MeSH
- TP63 protein, human MeSH Browser
- Transcription Factors MeSH
Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.
2nd Medical Department University Hospital Schleswig Holstein Kiel Germany
Department of Haematology Royal Bournemouth Hospital Bournemouth UK
Department of Immunotechnology Faculty of Engineering Lund University Sweden
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece
Hematology Department and University Pierre et Marie Curie Paris France
Hematology Department Nikea General Hospital Athens Greece
Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece
Laboratory of Biological Chemistry Medical School Aristotle University of Thessaloniki Greece
References provided by Crossref.org
DNA Demethylation Switches Oncogenic ΔNp63 to Tumor Suppressive TAp63 in Squamous Cell Carcinoma
DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy
