title: Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma.
abstract: Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL.
authors.affiliation: Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Sergey W
authors.initials: SW
authors.lastname: Popov
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Beate
authors.initials: B
authors.lastname: Wotschke
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Barth
authors.forename: Karola
authors.initials: K
authors.lastname: Dorsch
authors.forename: Olga
authors.initials: O
authors.lastname: Ritz
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
mesh_terms: D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D006801:Humans; D017578:Immunoglobulin Class Switching; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008479:Mediastinal Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase