title: Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection.
abstract: We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.
authors.affiliation: Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA.
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.forename: Sonia
authors.initials: S
authors.lastname: Jain
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Greaves
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology; D022801:Complementarity Determining Regions; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000276:immunology*; D017720:Molecular Epidemiology; D011379:Prognosis
chemical_list: D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region