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Subset #6 (IGHV1\u201069\/IGKV3\u201020) is less aggressive compared to subset #8 (IGHV4\u201039\/IGKV1(D)\u201039) 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\u2010wide DNA methylation profiles in subsets #6 and #8 as well as other U\u2010CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U\u2010CLL 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 <jats:italic>TP63<\/jats:italic> gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed <jats:italic>TP63<\/jats:italic> mRNA overexpression in additional nonsubset U\u2010CLL 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\u2010survival effect was also supported by siRNA\u2010mediated 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.<\/jats:p>","DOI":"10.1002\/ijc.31999","type":"journal-article","created":{"date-parts":[[2018,11,17]],"date-time":"2018-11-17T06:20:31Z","timestamp":1542435631000},"page":"2695-2706","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Integrated epigenomic and transcriptomic analysis reveals <i>TP63<\/i> as a novel player in clinically aggressive chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"144","author":[{"given":"Nikos","family":"Papakonstantinou","sequence":"first","affiliation":[{"name":"Institute of Applied Biosciences Centre for Research and Technology Hellas  Thessaloniki Greece"},{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala University  Uppsala 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