Clonal evolution of a follicular lymphoma: evidence for antigen selection.

Abstract

The potential role antigens play in growth stimulation or in clonal selection of follicular lymphomas is unknown. To study this issue, we sequenced the immunoglobulin heavy chain variable region genes expressed by a foflicular lymphoma from multiple biopsy specimens and also cloned and sequenced the corresponding germ-line variable gene from this patient. Comparison to the germ-line gene revealed numerous nucleotide substitutions in all of the lymphoma variable gene sequences. Some of the substitutions may have occurred in the nonmalignant precursor B cell that gave rise to this lymphoma because they were shared among all of the variable genes, but many of the mutations accumulated as the malignant done expanded. The mutations were distributed in such a way that strongly suggested the majority of tumor cells had been positively selected through their antigen receptor. This was especially evident for the mutations that developed late in the clonal evolution of this lymphoa. These findings indicate that antigen stimulation may be involved in the growth of folcular lymphoma tumors.

t(14;18), a journey to eternity

“…Follicular NHL cells are frozen in the centroblastic/centrocytic differentiation stage in which the somatic mutation machinery remains active. [61][62][63][64] The somatic mutation profiles of follicular NHL cells provide evidence that these neoplastic cells remain under continuous affinity selection, 65,66 so antigen-driven proliferation processes are most likely involved in the maintenance of the malignant cell population. 20 Bcl-2 transgenic mice are excellent tools to demonstrate the tumorigenicity of deregulated bcl-2 gene expression.…”

AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity

“…2 The process of somatic mutation may lead to intraclonal sequence heterogeneity demonstrated by the presence of unique somatic mutations scattered within the sequence of clonal IgV of individual B cells, as is observed in GC-derived lymphomas (follicle center lymphomas (FCL) and germinal center B-cell (GCB)-like diffuse large-cell lymphomas). [3][4][5] In normal GCB-lymphocytes SHM has so far been shown to act on the IgV, BCL6 and FAS genes, 2,6,7 while in diffuse large B-cell lymphomas (DLBCL) this process has been shown to affect additional genes (PIM1, PAX5, RhoH/TTF, cMYC). 8 Activation-induced cytidine deaminase (AID or AICDA) is specifically expressed in normal GC-lymphocytes and is necessary for SHM and for class switch recombination (CSR).…”

Molecular definition of the germinal centre stage of B–cell differentiation

“…Follicular lymphomas expressed most of the genes within the germinal centre B-cell signature suggesting that this malignancy arises from a germinal centre B cell per se. In keeping with this notion, follicular lymphomas are capable of ongoing somatic hypermutation of their immunoglobulin genes (Bahler & Levy 1992), demonstrating that certain normal functions of germinal centre B cells are maintained even after oncogenic transformation. Indeed, the sustained expression of germinal centre genes in follicular lymphomas suggests that these malignant cells retain much of the biology of normal germinal centre B cells.…”