title: Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones.
abstract: In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.
authors.affiliation: sarka.pospisilova@fnbrno.cz.
authors.forename: Karla
authors.initials: K
authors.lastname: Plevova
authors.forename: Hana Skuhrova
authors.initials: HS
authors.lastname: Francova
authors.forename: Katerina
authors.initials: K
authors.lastname: Burckova
authors.forename: Yvona
authors.initials: Y
authors.lastname: Brychtova
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.forename: Sarka
authors.initials: S
authors.lastname: Pavlova
authors.forename: Jitka
authors.initials: J
authors.lastname: Malcikova
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.forename: Boris
authors.initials: B
authors.lastname: Tichy
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
mesh_terms: D001402:B-Lymphocytes; D018572:Disease-Free Survival; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000401:mortality; D008297:Male; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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