Abstract
Key processes in the onset and evolution of chronic lymphocytic leukemia (CLL) are thought to include chronic (antigenic) activation of mature B cells through the B cell receptor (BcR), signals from the microenvironment, and acquisition of genetic alterations. Here we describe three families in which two or more siblings were affected by CLL. We investigated whether there are immunogenetic similarities in the leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain gene rearrangements of the siblings in each family. Furthermore, we performed array analysis to study if similarities in CLL-associated chromosomal aberrations are present within each family and screened for somatic mutations using paired tumor/normal whole-genome sequencing (WGS). In two families a consistent IGHV gene mutational status (one IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third family with four affected siblings was characterized by usage of the lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently described clinically aggressive IGLV3-21R110 subset. In this family, the CLL-specific rearrangements in two siblings could be assigned to either stereotyped subset #2 or the immunogenetically related subset #169, both of which belong to the broader IGLV3-21R110 subgroup. Consistent patterns of cytogenetic aberrations were encountered in all three families. Furthermore, the CLL clones carried somatic mutations previously associated with IGHV mutational status, cytogenetic aberrations and stereotyped subsets, respectively. From these findings, we conclude that similarities in immunogenetic characteristics in familial CLL, in combination with genetic aberrations acquired, point towards shared underlying mechanisms behind CLL development within each family.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries [1]
3 consisted of two brothers and two sisters with CLL, who were diagnosed in the age range from 64 until 81 years (Figure 1C)
We describe three families that represent distinct immunogenetic subgroups of CLL, presenting a unique opportunity to study the contribution of genetics and immunogenetics in CLL pathobiology
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries [1]. No single genetic lesion drives CLL, a range of recurrent cytogenetic aberrations and somatic mutations have been identified in CLL [2,3,4]. Cytogenetic aberrations are common in CLL, with around 80% of CLL patients carrying at least one of the four common chromosomal alterations, i.e. del(13q), del(11q), del(17p) and trisomy 12 [2, 5]. Of these four alterations, del(13q) is the most frequent and, as a sole aberration, is associated with indolent disease [6]. The majority of these putative CLL driver mutations are present at low frequency (
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