Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
| Autor: | Frederic Davi, Davide Rossi, Sara Ek, Chrysoula Belessi, Matthias Ritgen, Andigoni Malousi, Nikos Papakonstantinou, Gianluca Gaidano, Larry Mansouri, Karla Plevová, Anastasia Hadzidimitriou, Šárka Pospíšilová, Maria Tsagiopoulou, Kostas Stamatopoulos, Martí Duran-Ferrer, Maria Gounari, Sujata Bhoi, Venera Kuci‐Emruli, Christiane Pott, Stamatia Laidou, Theodoros Moysiadis, Paolo Ghia, José I. Martín-Subero, Richard Rosenquist, Fotis Psomopoulos, Konstantinos Pasentsis, Zadie Davis, David Oscier, Stavroula Ntoufa, Niki Stavroyianni, Despoina Papazoglou |
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| Přispěvatelé: | Papakonstantinou, Niko, Ntoufa, Stavroula, Tsagiopoulou, Maria, Moysiadis, Theodoro, Bhoi, Sujata, Malousi, Andigoni, Psomopoulos, Foti, Mansouri, Larry, Laidou, Stamatia, Papazoglou, Despoina, Gounari, Maria, Pasentsis, Konstantino, Plevova, Karla, Kuci-Emruli, Venera, Duran-Ferrer, Marti, Davis, Zadie, Ek, Sara, Rossi, Davide, Gaidano, Gianluca, Ritgen, Matthia, Oscier, David, Stavroyianni, Niki, Pospisilova, Sarka, Davi, Frederic, Ghia, Paolo, Hadzidimitriou, Anastasia, Belessi, Chrysoula, Martin-Subero, Jose I, Pott, Christiane, Rosenquist, Richard, Stamatopoulos, Kostas |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Epigenomics
Male Cancer Research Chronic lymphocytic leukemia B-cell receptor Primary Cell Culture Somatic hypermutation Receptors Antigen B-Cell Apoptosis Biology CLL stereotypy DNA methylation gene expression TP63 03 medical and health sciences 0302 clinical medicine immune system diseases hemic and lymphatic diseases medicine Tumor Cells Cultured Humans RNA Small Interfering Promoter Regions Genetic Gene Sequence Analysis RNA Gene Expression Profiling Tumor Suppressor Proteins breakpoint cluster region DNA Methylation medicine.disease Leukemia Lymphocytic Chronic B-Cell 3. Good health Up-Regulation Gene Expression Regulation Neoplastic Real-time polymerase chain reaction Oncology 030220 oncology & carcinogenesis Cancer research Female Transcription Factors |
| Zdroj: | International journal of cancer International Journal of Cancer |
| Popis: | 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. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL. |
| Databáze: | OpenAIRE |
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