title: Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status.
abstract: We recently reported that Swedish VH3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite VH mutation status. To investigate this further, we analyzed the VH and VL gene rearrangements in 90 VH3-21+ patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated VH genes and 37% unmutated VH genes. Fifty (56%) patients displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif DANGMDV. Also, a highly biased Vlambda2-14 use was evident in 72% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although VH3-21+ CLLs have a remarkably predominant lambda expression, analyses of kappa deleting element indicated a conserved light-chain rearrangement order. The overall survival was poor in the VH3-21+ cohort (median survival, 88 months), with no significant difference in relation to mutation status or CDR3 homology. High ZAP-70 and CD38 expression was found in both mutated and unmutated VH3-21+ cases as well as a slight increase of 11q-aberrations. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21+ CLLs independent of geographic origin and mutation status.
authors.affiliation: Department of Genetic and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Thorsélius
authors.forename: Alexander
authors.initials: A
authors.lastname: Kröber
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.forename: Dirk
authors.initials: D
authors.lastname: Kienle
authors.forename: Emilia
authors.initials: E
authors.lastname: Albesiano
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.forename: Lan-Phuong
authors.initials: LP
authors.lastname: Dao-Ung
authors.forename: James
authors.initials: J
authors.lastname: Wiley
authors.forename: Juhani
authors.initials: J
authors.lastname: Vilpo
authors.forename: Anna
authors.initials: A
authors.lastname: Laurell
authors.forename: Mats
authors.initials: M
authors.lastname: Merup
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Karin
authors.initials: K
authors.lastname: Karlsson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000595:Amino Acid Sequence; D001315:Australia; D002869:Chromosome Aberrations; D005060:Europe; D005843:Geography; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008969:Molecular Sequence Data; D009154:Mutation; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States
chemical_list: D007128:Immunoglobulin Fragments; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains