Genetic, transcriptomic and epigenetic analysis of chronic lymphocytic leukemia and its transformation into Richter’s syndrome

The chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that affects more commonly the elderly. It is characterized by CD5 and CD23 positive B lymphocytes and it shows a heterogeneous clinical and biological behaviour. Actually, based on the status of mutations in the immunoglobulin heavy chain variable region (IgHV) genes, it is possible to define two subgroups, each of them carrying different somatic variations. In a small, but significant, number of cases, CLL can progress into an aggressive lymphoma, Richter’s syndrome (RS), characterized by a poor outcome and an overall short survival. RS cells typically show an accumulation of specific mutations, some of them already present in the original CLL clone, while others are progressively acquired during transformation. The aim of this work is to discuss and pinpoint some specific features regarding the genome, the transcriptome and the epigenome of these two diseases. The topic has been chosen since the laboratory where I have done my internship is actively working on the characterization of RS cells from the genetic, epigenetic and transcriptomic points of view in a translational perspective, taking advantage of patient-derived xenograft models. To this purpose, the dissertation starts presenting the transcriptome of CLL, focusing on the expression landscape, the splice forms and chimeras. Then, the attention has been pointed on the epigenome of this disorder, analysing the regulatory regions together with potential alterations affecting them and the regulatory chromatin landscape in pathological conditions. Based on different transcriptional and epigenetic features, two clusters, C1 and C2, have been distinguished and described. Finally, the transformation of CLL into Richter’s syndrome has been taken into consideration, analysing the genetic and transcriptomic features of these cells. Up to now, no epigenetic results on RS have been reported. Several molecular and biological aspects of RS are still missing, underlining the need for further studies to better understand the clinical behaviour of this aggressive transformation and identify novel therapeutic approaches.