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

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

Department of Haematology Royal Bournemouth Hospital Bournemouth UK

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Immunotechnology Faculty of Engineering Lund University Sweden

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Division of Experimental Oncology Department of Onco Hematology IRCCS San Raffaele Scientific Institute and Università Vita Salute San Raffaele Milan Italy

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont Novara Italy

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

Hematology Oncology Institute of Southern Switzerland and Institute of Oncology Research Bellinzona Switzerland

Institut d'Investigacions Biomèdiques August Pi i Sunyer Departamento de Fundamentos Clínicos Universitat de Barcelona Barcelona Spain

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

Laboratory of Biological Chemistry Medical School Aristotle University of Thessaloniki Greece

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