Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas.
Activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM), class switch recombination (CSR), and immunoglobulin gene conversion in B-lymphocytes. Here we report for the first time the expression of AID in healthy human B-lymphocytes and in B-cell non-Hodgkin lymphomas (B-NHL). AID mRNA expression in humans is restricted to the CD19(+)CD38(+)IgD(-) germinal center cells, namely the CD19(+)CD38(+)CD44(-) centroblasts. After in vitro stimulation of naive human B cells by CD40-L and IL-4, AID mRNA is strongly induced for only 48 hours. In a survey of human B-NHL AID was found to be constitutively expressed in follicular lymphoma and in diffuse large B-cell lymphoma but to be absent in B-precursor lymphoblastic leukemia, in mantle cell lymphoma, and in plasma cell myeloma. In B-cell chronic lymphatic leukemia, in immunocytoma, and in extranodal marginal zone B-cell lymphoma of MALT, AID mRNA was expressed only in some samples. In follicular lymphoma and diffuse large B-cell lymphoma, the expression of AID mRNA was coincident with the presence of SHM in the variable region exons of the immunoglobulin heavy-chain gene. In human B-NHL, the AID mRNA is spliced into 4 different variants but does not contain point mutations. Thus AID, which is highly regulated during healthy B-cell development, is constitutively expressed in human germinal center B-NHL and in subsets of nongerminal center B-NHL. This constitutive expression of AID may promote illegitimate DNA recombinations and somatic mutations in B-NHL.
Greeve
Jobst
J
Zentrum für Innere Medizin, Medizinische Klinik I, Universitätsklinikum Hamburg-Eppendorf, Germany. jobst.greeve@insel.ch
Philipsen
Antje
A
Krause
Kristina
K
Klapper
Wolfram
W
Heidorn
Klaus
K
Castle
Brian E
BE
Janda
Joe
J
Marcu
Kenneth B
KB
Parwaresch
Reza
R
D036541:ADP-ribosyl Cyclase / Q000032:analysis; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000032:analysis; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000201:enzymology*; D023201:CD40 Ligand / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D054278:Embryonal Carcinoma Stem Cells; D004790:Enzyme Induction / Q000187:drug effects; D005091:Exons / Q000235:genetics; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology; D016393:Lymphoma, B-Cell / Q000201:enzymology*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000201:enzymology; D008224:Lymphoma, Follicular / Q000201:enzymology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000201:enzymology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000096:biosynthesis; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D015703:Antigens, CD; D018941:Antigens, CD19; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D023201:CD40 Ligand; D015847:Interleukin-4; D000074462:Positive Regulatory Domain I-Binding Factor 1; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase