Epstein-Barr virus-transformed pro-B cells are prone to illegitimate recombination between the switch region of the mu chain gene and other chromosomes.

Abstract

Six independently maintained sublines of FLEB 14, a fetal-liver-derived Epstein-Barr virus-transformed pro-B cell line that has not yet rearranged its immunoglobulin genes, were examined after in vitro propagation during 19-36 months. Two lines showed no immunoglobulin heavy chain gene rearrangement, whereas one allele was rearranged with breakpoints inside the switch region of the mu chain gene in the remaining four. These rearrangements had been generated by the translocation of different chromosome fragments to the immunoglobulin heavy chain gene cluster-carrying 14q32 band in each of the four lines. Previously, a similar rearrangement was found in a fifth subline concurrently with a reciprocal 6;14 translocation. The transposed pieces have been derived from chromosomes 16 and 18 in two of the more recently rearranged lines. Their origins could not be determined in the remaining two lines, but they were different from each other and the other three 14q+ markers. The 14q+ marker-carrying variant has replaced its diploid progenitor suggesting that the translocation has conveyed some in vitro growth advantage on its carrier. This was also supported by the duplication of the 14q+ marker and the loss of its normal chromosome 14 homologue in one subline during serial culturing. The vulnerability of the switch region of the mu chain gene to illegitimate recombination at the pro-B stage and the possible relevance of this finding for the origin of the Burkitt lymphoma-associated 8;14 (immunoglobulin heavy chain gene cluster/MYC) translocation is discussed.

Host-cell-phenotype-dependent control of the BCR2/BWR1 promoter complex regulates the expression of Epstein-Barr virus nuclear antigens 2-6.

“…These are particular cell types that may provide clues to the mechanisms governing BCR2/BWR1 promoter switch. FLEB 14-6 is a LCL ofpro-B origin with no immunoglobulin gene rearrangement (19) and with an intact BCR2 from the B95-8 virus. Transcriptional control in this line has prevented the switch from BWR1 to BCR2.…”

Clonal lymphoid progenitor cell lines expressing the BCR/ABL oncogene retain full differentiative function.

“…GL, germ line. (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) 600 (100-1250) <50 Mice were analyzed 8-10 weeks after reconstitution. Data represent the average of 2-4 mice in control groups and 8-10 mice in experimental groups.…”

“…One approach to this problem has been to manipulate long-term bone-marrow culture conditions to selectively expand B-cell progenitors (7). Another approach has been to immortalize the progenitor cells by virus transformation (8)(9)(10). Most of this work has used Abelson murine leukemia virus as the transforming agent.…”

X-linked lymphoproliferative disease (XLP) as a model of Epstein-Barr virus-induced immunopathology

“…The Bcl-2 gene appears to act similarly, in some respects, to EBV in that programmed cell death (apoptosis) is prevented by Bcl-2 and also by infecting B cells with EBV [17]. Finally, the in vitro studies by Klein's group [2] have demonstrated a tendency of pro-B cells infected with EBV to develop genetic mistakes involving the switch mu region in chromosome 14. Thus, they have hypothesized that the target cell for the translocations involved in BL are pro-B cells (Fig.…”