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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2679-2687
Molecular Analysis of Single B Cells From T-Cell-Rich B-Cell
Lymphoma Shows the Derivation of the Tumor Cells From Mutating
Germinal Center B Cells and Exemplifies Means by Which
Immunoglobulin Genes Are Modified in Germinal Center B Cells
Andreas Bräuninger,
Ralf Küppers,
Tilmann Spieker,
Reiner Siebert,
John G. Strickler,
Brigitte Schlegelberger,
Klaus Rajewsky, and
Martin-Leo Hansmann
From the Department of Pathology, University of Frankfurt, Frankfurt;
the Institute for Genetics, University of Cologne, Cologne; the
Department of Human Genetics, University of Kiel, Kiel, Germany; and
the Department of Pathology, Mayo Clinic, Rochester, MN.
T-cell-rich B-cell lymphoma (TCRBCL) belongs to the group of
diffuse large cell lymphomas (DLL). It is characterized by a small
number of tumor B cells among a major population of nonmalignant polyclonal T cells. To identify the developmental stage of the tumor
progenitor cells, we micromanipulated the putative neoplastic large
CD20+ cells from TCRBCLs and amplified and sequenced
immunoglobulin (Ig) V gene rearrangements from individual cells. In six
cases, clonal Ig heavy, as well as light chain, gene rearrangements
were amplified from the isolated B cells. All six cases harbored
somatically mutated V gene rearrangements with an average mutation
frequency of 15.5% for heavy (VH) and 5.9% for light
(VL) chains and intraclonal diversity based on somatic
mutation. These findings identify germinal center (GC) B cells as the
precursors of the transformed B cells in TCRBCL. The study also
exemplifies various means how Ig gene rearrangements can be modified by
GC B cells or their malignant counterparts in TCRBCL: In one case, the
tumor precursor may have switched from  to  light chain
expression after acquiring a crippling mutation within the initially
functional light chain gene. In another case, the tumor cells
harbor two in-frame VH gene rearrangements, one of which
was rendered nonfunctional by somatic mutation. Either the tumor cell
precursor entered the GC with two potentially functional in-frame
rearrangements or the second VHDHJH
rearrangement occurred in the GC after the initial in-frame
rearrangement was inactivated by somatic mutation. Finally, in each of
the six cases, at least one cell contained two (or more) copies of a
clonal Ig gene rearrangement with sequence variations between these
copies. The presence of sequence variants for V region genes within
single B cells has so far not been observed in any other normal or
transformed B lymphocyte. Fluorescence in situ hybridization (FISH)
points to a generalized polyploidy of the tumor cells.
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