Chronic lymphocytic leukaemia (CLL) is a common form of B-cell leukaemia, of unknown aetiology, which has the strongest hereditary component amongst lymphoproliferative disorders. A key finding regarding CLL cells is that they derive from autoreactive B lymphocytes, possess stereotyped antibody (Ab) structures, and exhibit polyreactivity and autoreactivity.

The long-term aim is to prevent CLL through a better understanding of the biological mechanisms underlying its development.

The hypothesis is that a hereditary predisposition to CLL causes alterations in pre-leukaemic B cells due to impaired immune tolerance, ultimately promoting transformative events that give rise to CLL. These alterations modify the immunoglobulin (Ig) repertoires, leading to an enrichment of specific B-cell rearrangements associated with abnormal antibody reactivity. 

The overall aim of this study is to understand the role of hereditary predisposition to CLL in the alteration of the structural immunoglobulin repertoire and to determine at which stages of maturation and in which B-cell subpopulations these alterations occur. Specific objective: to define a B-cell receptor (BCR) repertoire associated with CLL through the analysis of non-leukaemic B cells from patients with CLL.

To this end, the project involves high-throughput sequencing of BCR immunoglobulins in non-leukaemic B cells from patients with familial and sporadic CLL. The alterations identified in the immunoglobulin heavy chain (IGH) repertoires of patients compared with controls are used to define a CLL-associated repertoire. It is expected that differences will be identified in the IGH repertoire of CLL patients, leading to the emergence of mature B cells characterised by specific rearrangements that are normally absent.

This approach to studying CLL within a familial context differs significantly from previous studies, as it does not aim to identify genetic alterations but focuses on the structural and functional characteristics of non-leukaemic B cells. Furthermore, it avoids the background noise caused by alterations specific to the leukaemic clone.

The study sheds light on the fundamental functional abnormalities of B cells that lead to the development of CLL and identifies its cellular origin, thereby providing the basis for the development of new prevention and treatment strategies.