title: Intraclonal cell expansion and selection driven by B cell receptor in chronic lymphocytic leukemia.
abstract: The mutational status of the immunoglobulin heavy-chain variable region (IGHV) genes utilized by chronic lymphocytic leukemia (CLL) clones defines two disease subgroups. Patients with unmutated IGHV have a more aggressive disease and a worse outcome than patients with cells having somatic IGHV gene mutations. Moreover, up to 30% of the unmutated CLL clones exhibit very similar or identical B cell receptors (BcR), often encoded by the same IG genes. These "stereotyped" BcRs have been classified into defined subsets. The presence of an IGHV gene somatic mutation and the utilization of a skewed gene repertoire compared with normal B cells together with the expression of stereotyped receptors by unmutated CLL clones may indicate stimulation/selection by antigenic epitopes. This antigenic stimulation may occur prior to or during neoplastic transformation, but it is unknown whether this stimulation/selection continues after leukemogenesis has ceased. In this study, we focused on seven CLL cases with stereotyped BcR Subset #8 found among a cohort of 700 patients; in six, the cells expressed IgG and utilized IGHV4-39 and IGKV1-39/IGKV1D-39 genes, as reported for Subset #8 BcR. One case exhibited special features, including expression of IgM or IgG by different subclones consequent to an isotype switch, allelic inclusion at the IGH locus in the IgM-expressing cells and a particular pattern of cytogenetic lesions. Collectively, the data indicate a process of antigenic stimulation/selection of the fully transformed CLL cells leading to the expansion of the Subset #8 IgG-bearing subclone.
authors.affiliation: Division of Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova, Italy. monica.colombo@istge.it
authors.forename: Monica
authors.initials: M
authors.lastname: Colombo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cutrona
authors.forename: Daniele
authors.initials: D
authors.lastname: Reverberi
authors.forename: Sonia
authors.initials: S
authors.lastname: Fabris
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quintana
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarta
authors.forename: Fabio
authors.initials: F
authors.lastname: Ghiotto
authors.forename: Franco
authors.initials: F
authors.lastname: Fais
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D027041:Somatic Hypermutation, Immunoglobulin; D014443:Tyrosine / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D018985:Epitopes, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine