Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia
Frontiers in Oncology, vol. 11, pp. 740083
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.
Authors 13
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Affiliation as printed
Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Affiliation as printed
Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Uppsala University · Karolinska University Hospital · Science for Life Laboratory · Karolinska Institutet
Affiliation as printed
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Solna, Sweden
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National and Kapodistrian University of Athens · Centre for Research and Technology Hellas
Affiliation as printed
Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
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Affiliation as printed
Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Affiliation as printed
Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Central European Institute of Technology – Masaryk University
Affiliation as printed
CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia
CEITEC – Central European Institute of Technology, Masaryk University, Brno, Czechia
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Affiliation as printed
Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, LUMC, Leiden, Netherlands
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Solna, Sweden
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Anton W. Langerak corresponding
Affiliation as printed
Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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