title: AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells.
abstract: The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL.
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Huemer
authors.forename: Stefan
authors.initials: S
authors.lastname: Rebhandl
authors.forename: Nadja
authors.initials: N
authors.lastname: Zaborsky
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Gassner
authors.forename: Stefan
authors.initials: S
authors.lastname: Hainzl
authors.forename: Lukas
authors.initials: L
authors.lastname: Weiss
authors.forename: Daniel
authors.initials: D
authors.lastname: Hebenstreit
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Roland
authors.initials: R
authors.lastname: Geisberger
mesh_terms: D051940:B7-2 Antigen / Q000276:immunology*; D049109:Cell Proliferation; D003564:Cytidine Deaminase / Q000276:immunology*; D004249:DNA Damage / Q000276:immunology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D050438:Genes, Immunoglobulin Heavy Chain / Q000276:immunology; D006657:Histones / Q000276:immunology; D006801:Humans; D007134:Immunoglobulin Switch Region / Q000276:immunology; D007148:Immunoglobulin mu-Chains / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051940:B7-2 Antigen; C497964:CD86 protein, human; C468783:H2AX protein, human; D006657:Histones; D007148:Immunoglobulin mu-Chains; D009363:Neoplasm Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: Activation-induced deaminase (AID) • CD86 • Chronic lymphocytic leukemia (CLL) • Clonal evolution • Mutation