Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders.
Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations.
Capello
Daniela
D
Department of Clinical and Experimental Medicine & IRCAD, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Cerri
Michaela
M
Muti
Giuliana
G
Lucioni
Marco
M
Oreste
Pierluigi
P
Gloghini
Annunziata
A
Berra
Eva
E
Deambrogi
Clara
C
Franceschetti
Silvia
S
Rossi
Davide
D
Alabiso
Oscar
O
Morra
Enrica
E
Rambaldi
Alessandro
A
Carbone
Antonino
A
Paulli
Marco
M
Gaidano
Gianluca
G
D017209:Apoptosis / Q000235:genetics; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics*; D016377:Organ Transplantation; D051562:Proto-Oncogene Proteins c-bcr / Q000096:biosynthesis / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr