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Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia |
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| Authors: | Nikos Papakonstantinou Stavroula Ntoufa Maria Tsagiopoulou Theodoros Moysiadis Sujata Bhoi Andigoni Malousi Fotis Psomopoulos Larry Mansouri Stamatia Laidou Despoina Papazoglou Maria Gounari Konstantinos Pasentsis Karla Plevova Venera Kuci-Emruli Marti Duran-Ferrer Zadie Davis Sara Ek Davide Rossi Gianluca Gaidano Matthias Ritgen David Oscier Niki Stavroyianni Sarka Pospisilova Frederic Davi Paolo Ghia Anastasia Hadzidimitriou Chrysoula Belessi Jose I Martin-Subero Christiane Pott Richard Rosenquist Kostas Stamatopoulos |
| Affiliation: | 1. Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece;2. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden;3. Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Greece;4. Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;5. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;6. Center of Molecular Biology and Gene Therapy, Department of Internal Medicine–Hematology and Oncology, University Hospital Brno and Medical Faculty of the Masaryk University, Brno, Czech republic;7. Department of Immunotechnology, Faculty of Engineering, Lund University, Sweden;8. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain;9. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK;10. Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland;11. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;12. Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany;13. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece;14. Hematology Department and University Pierre et Marie Curie, Paris, France;15. Division of Experimental Oncology, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy;16. Hematology Department, Nikea General Hospital, Athens, Greece |
| Abstract: | 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. |
| Keywords: | CLL stereotypy DNA methylation gene expression TP63 |