title: Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia.
abstract: Hairy cell leukemia (HCL) is thought to arise from a post-germinal center (GC) B-cell, however the exact normal counterpart remains unclear. We performed VH gene analysis of 32 HCL cases, revealing somatically mutated VH genes (<98% homology) in 27 cases and unmutated VH genes in five cases, four of which displayed germline VH genes. Intraclonal heterogeneity was evident in the majority of eight mutated HCLs investigated, although at a lower level compared to GC-derived lymphomas. A novel finding of preferential VH3-30 gene usage was detected (19% of HCLs). Our data confounds the postulated post-GC origin in HCL considering (1) the finding of unmutated HCLs, generally correlating with a pre-GC origin, and (2) the presence of intraclonal variation in mutated HCLs. The latter suggests that the transformed B-cell was frozen when it still had an active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted VH3-30 usage indicates that antigen selection could be a promoting factor in HCL development.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratary, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Thorsélius
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Walsh
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Hans
authors.initials: H
authors.lastname: Hagberg
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000032:analysis / Q000235:genetics*; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*
chemical_list: D007143:Immunoglobulin Heavy Chains