Analysis of immunoglobulin heavy and light chain variable genes in post‐transplant lymphoproliferative disorders

Abstract

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.

Genetic and phenotypic analysis of B‐cell post‐transplant lymphoproliferative disorders provides insights into disease biology

“…While similar to earlier studies [52,53], a more recent report described a higher frequency of sIg L loss (%76%) based on IHC staining [54]. These discrepancies may be due to lower sensitivity of IHC-based methods compared to flow cytometry, as has been reported for other B-NHL [55].…”

“…In EBVþ PTLD, the virus itself may rescue B-cell clones, which lack evidence of antigen selection or have crippling Ig mutations [2,7,8], a hypothesis supported by recent in vitro experiments [11]. However, the finding of sIgÀ EBVÀ PTLD by us and others [54] suggests that as yet unknown molecular alterations of the neoplastic cells may allow survival of EBVÀ BCR-deficient lymphocytes.…”

“…Capello et al recently reported crippling mutations in Ig L genes [54]. Since we did not analyse mutations in Ig L genes, it is unclear whether cytoplasmic light chain expression, as observed in two of our sIg H þ sIg L À PTLD, is due to Ig L gene mutations or other aberrations.…”

Array-Based Comparative Genomic Hybridization Analysis Reveals Chromosomal Copy Number Aberrations Associated with Clinical Outcome in Canine Diffuse Large B-Cell Lymphoma

“…A recent study [27] also demonstrated that MYC translocation with IG partner gene has a negative prognostic impact compared with non IG-MYC translocation. IGHV, IGK variable (IGKV) and IGL variable (IGLV) genes inactivation through destructive mutations is a well-known event also in post-transplant lymphoproliferative disorders (PTLDs), in particular in those originating from Germinal Center B cells [28]. Taken together, these evidences clearly demonstrate that in both dogs and humans IG heavy and light chain loci are commonly inactivated, possibly playing an essential role in DLBCL pathogenesis.…”

Post-transplant lymphoproliferative disorders

“…25 About ¼ of cases have unmutated IGV (immunoglobulin gene variable regions). In most cases the IGV are mutated, but without on-going mutations, 26,27 The only oncogene that is occasionally involved is BCL6, which may show somatic hypermutation or aberrant methylation of the promoter region. 24,26 Cytogenetic aberrations can be detected but are less common than in M-PTLD.…”