Incidence of novel N‐glycosylation sites in the B‐cell receptor of lymphomas associated with immunodeficiency

Abstract

Summary Novel N‐glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B‐cell lymphomas (DLBCL) parallels the known heterogenity of the disease. Immunodeficiency‐related non‐Hodgkin's lymphomas (NHL) include post‐transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome‐related NHL (AIDS‐NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS‐NHL carry mutated VH genes and variable features of GC or post‐GC cells. To determine if N‐glycosylation is a feature of immunodeficiency‐related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS‐NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells (P = 0·15). AIDS‐NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N‐glycosylation sites in PTLD, consistent with post‐GC features. The variable incidence of N‐glycosylation sites in AIDS‐NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development.

Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

“…11 Additionally, in the present large series of HCL, we observed an irrelevant incidence of novel N-glycosylation sites introduced by somatic mutation in the tumor IgV region (<6%), similar to that observed in normal memory B cells or in transformed memory and marginal zone B cells (Online Supplementary Tables S1 and S2). 5,6,19,53 Since N-glycosylation sites are specifically introduced in the IgV region of germinal center-derived lymphomas, while they are rare in marginal zone or post-germinal center B-cell neoplasms, 5,6,19,53 our results provide further support to the hypothesis that HCL originates from non-germinal center derived B cells.…”

“…36 Clearly, the selective influences active in HCL appear to follow routes that are different from those of other B-cell neoplasms, in particular from the extensively investigated IgMpositive chronic lymphocytic leukemia (CLL). 19 For example, IGHV1-69 was totally absent in HCL from our and previously published series (total 164 IgHV sequences), 2,7,8,21,22,37 while it dominates the unmutated subset in CLL (Online Supplementary Figures S1A and S1B). 19 Similarly, IGHV4-34 is used predominantly in a mutated conformation by CLL, but was preferentially unmutated in the HCL cases in our series ( Figure 5A), and even more significantly when all published HCL sequences were pooled (p=0.0002).…”

“…19 For example, IGHV1-69 was totally absent in HCL from our and previously published series (total 164 IgHV sequences), 2,7,8,21,22,37 while it dominates the unmutated subset in CLL (Online Supplementary Figures S1A and S1B). 19 Similarly, IGHV4-34 is used predominantly in a mutated conformation by CLL, but was preferentially unmutated in the HCL cases in our series ( Figure 5A), and even more significantly when all published HCL sequences were pooled (p=0.0002). 2,7,8,21,22,37 Lack of apparent HCDR3 stereotypy in HCL is another feature of variance with CLL, which, conversely, frequently groups cases with shared HCDR3 structural features.…”

“…Second, cloning of IGV region transcripts confirms the existence of low levels of intraclonal heterogeneity also in cases with 98% ≤ homology <100% to germline. 19 Third, the vast majority (82%) of HCL co-express multiple pre-switch (IgM±D) and postswitch (IgG±A) sIgH, independently of mutational status and while activation-induced cytidine deaminase is expressed. 2 Histological findings and lack of CD27 and CD38 suggest that, in typical HCL, the mutational and switch events are unlikely to occur in the germinal cen- ter.…”

“…The incidence of potential novel N-glycosylation sites in IGHVDJ, IGKVJ and IGLVJ transcript sequences was assessed as previously described. 6,19 Statistical analyses were performed using χ 2 or Fisher's exact tests. p values <0.05 were considered statistically significant.…”