Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma

Abstract

Further understanding of the nature of the cell of origin in FL has been provided by analysis of the immunoglobulin variableregion gene sequences of the tumor cells. During differentiation, normal B lymphocytes undergo a series of recombinatorial and mutational changes in their immunoglobulin variable-region genes. The V(D)J rearrangements of V H and V L genes occur mainly in the bone marrow, and, after encounter with antigen, the somatic mutation mechanism is activated in centroblasts in the GC. [1][2][3] In this site, certain mutated sequences are selected by antigens held on follicular dendritic cells, leading to affinity maturation of the antibody response. Survival, maturation, and subsequent fate of selected B cells are directed by several additional elements in the GC, including CD40L ϩ T cells and cytokine milieu. [1][2][3] For FL, it is clear that the cell of origin has undergone somatic mutation and that in many patients this process has continued after transformation, leading to intraclonal variation of V gene sequences. [4][5][6] This behavior is consistent with location in the GC. Because normal B cells rely on engagement of the B-cell receptor for activation of the mutation mechanism, the finding of continuing mutational activity has led to debate about the role of antigens in stimulating FL. 7 However, it appears that ongoing mutational activity may be limited in FL, 8 but it is not apparent in cases that have transformed to diffuse lymphoma after chemotherapy. 5,9 Uncertainty about the role of antigen in FL also cannot easily be resolved by analysis of mutational patterns in V genes because it is now evident that there is a natural tendency of the complementaritydetermining region (CDR) sequences to accumulate replacement mutations. 10 It remains unclear, therefore, whether antigen has a role in influencing the behavior of tumor cells in FL.However, the importance of immunoglobulin expression in FL is highlighted by the fact that in most patients with FL, expression is retained, in spite of the fact that one allele of chromosome 14 is commonly disrupted at 14q32 by the t(14;18) translocation. 11,12 Consequent overexpression of bcl-2 protein by the nonfunctional immunoglobulin allele is one mechanism that contributes to tumor cell survival. The almost universal conservation of immunoglobulin expression by the remaining functional allele might indicate a selective advantage for tumor cells in FL. The question arises as to whether this is dependent on stimulation by antigen.Immunoglobulin carries N-glycosylated oligosaccharides located mainly in the heavy-chain constant regions. These act as spacers for the immunoglobulin molecule that are important for For personal use only. on May 11, 2018. by guest www.bloodjournal.org From maintaining effector functions. 13 Because of locations of the sites in the interstitial region between the C H 2 domains, the oligosaccharide chains are incompletely galactosylated and sialylated. 14 Human antibodies do not generally contain O-linked oligosaccharides, wi...

Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event?

“…1 We further showed that subsets of aggressive B NHL acquire sites 2 in contrast to sequences of myeloma, CLL and normal B cells where this is rare. 1 These data suggest positive selection and a critical role for the introduced glycosylation sites in the pathogenesis of FL.…”

“…To date, this mutation has not been reported in normal controls, lymphoid disorders or in patients with secondary erythrocytosis. [1][2][3][4][5][6][7][8][9][10] In this study, we have analyzed bone marrow or peripheral blood samples from 349 patients (PV, n ¼ 84; ET, n ¼ 243; IMF, n ¼ 22) referred to our diagnostic service for cytogenetic analysis and/or exclusion of the BCR-ABL fusion from several hospitals in the north of Spain between 1996 and 2005. Our study group thus includes the largest series of ET cases reported to date for JAK2 analysis.…”

Immunoglobulin heavy and light chain gene features are correlated with primary cold agglutinin disease onset and activity

“…We also investigated mutations in this sequence in previously published sequences as well as our own database and found it often mutated, most frequently at Ser (S), in normal B cells as well as in B-cell lymphoma. 3,7 This region seems to be highly conserved in IGHV4 family germline genes (Online Supplementary Figure S1). Analysis of the protein structure 8 shows that KLS amino acids are located at the protein surface, relatively close to the antigen-binding region at a distance similar to the I antigen-binding AVY hydrophobic patch ( Figure 1B).…”

Variations in “rescuability” of immunoglobulin molecules from different forms of human lymphoma: implications for anti-idiotype vaccine development

“…This phenomenon might imply that the most crucial step in this strategy for producing Id vaccine is the biological stabilization of an Id-secreting hybridoma. This is a problem that, per se, is not easily surmountable when dealing with rescue fusions and might even accelerate the transition towards recombinant technologies [23,24] Finally, at the time of writing it is not clear whether the recent identification of acquired, potential glycosylation sites within the amino acid sequences of tumor-specific immunoglobulins [25][26][27] may have an impact on either idiotypic vaccination as a whole or the choice of the methods by which the Id-containing immunoglobulin is rescued.…”