title: Telomeric IGH losses detectable by fluorescence in situ hybridization in chronic lymphocytic leukemia reflect somatic VH recombination events.
abstract: Routine interphase fluorescence in situ hybridization (FISH) analysis of chronic lymphocytic leukemia (CLL) with LSI IGH/CCND1 assay, applied to differentiate CLL from leukemic mantle cell lymphoma, identified a subset of cases (42/174) with translocation-like IGH signal pattern. To unravel the underlying 14q32/IGH aberrations, 14 of these cases were subjected to cytogenetic, detailed FISH, and V(H) mutation analyses. FISH identified cryptic losses of various portions of the IGHV region in all 14 cases. Fine mapping of these V(H) deletions revealed a strict correlation between their distal border and localization of the used VH gene, suggesting that they are not oncogenic but reflect physiological events accompanying somatic V-D-J assembly. This hypothesis was further supported by FISH analysis of 20 CLL and hairy cell leukemia cases with the known V(H) usage showing a constant loss of sequences proximal to the used gene, identification of V(H) deletions in normal B cells, and their exclusive demonstration in B cell malignancies, but not of T cell and myeloid linage. Given that these cryptic physiological VH losses in B cells may seriously complicate analysis of B cell leukemia/lymphoma and lead to false conclusions, FISH users should take them into consideration when interpreting IGH aberrations in these malignancies.
authors.affiliation: Center for Human Genetics, Catholoc University Leuven, Leuven, Belgium. iwona.wlodarska@uz.kuleuven.ac.be
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.forename: Christine
authors.initials: C
authors.lastname: Matthews
authors.forename: Ellen
authors.initials: E
authors.lastname: Veyt
authors.forename: Helena
authors.initials: H
authors.lastname: Pospisilova
authors.forename: Mark A
authors.initials: MA
authors.lastname: Catherwood
authors.forename: Tim S
authors.initials: TS
authors.lastname: Poulsen
authors.forename: Vera
authors.initials: V
authors.lastname: Vanhentenrijk
authors.forename: Rachel
authors.initials: R
authors.lastname: Ibbotson
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: T C M Curly
authors.initials: TC
authors.lastname: Morris
authors.forename: H Denis
authors.initials: HD
authors.lastname: Alexander
mesh_terms: D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004252:DNA Mutational Analysis; D003663:Decision Trees; D003937:Diagnosis, Differential; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009660:Northern Ireland; D011995:Recombination, Genetic / Q000235:genetics*; D016615:Telomere / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D007143:Immunoglobulin Heavy Chains