Conserved patterns of somatic mutation and secondary VH gene rearrangement create aberrant lg-encoding genes in Epstein-Barr virus-transformed and normal human B lymphocytes

• Published in: International immunology 1992-02, Vol.4 (2), p.197-206
• Main Authors: Brokaw, Jane L., Wetzel, Suzanne M., Pollok, Brian A.
• Format: Article
• Language: English
• Subjects: alternative RNA splicing; gene rearrangement; somatic mutation
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/4.2.197

Expression of N-terminal-truncated Ig heavy chains without normal light chain expression has been shown to occur In human B cell tumor lines, and to be due to diverse types of structural alteration within the expressed Ig heavy and light chain genes. Due to the tumor cell origin of these lines, generation of aberrant Ig-encoding genes may only occur after malignant transformation, reflecting the release of the tumor B cell from the need to express functional Ig for continued clonal proliferation. The genetic basis for expression of VH-truncated μ chains without light chains in several Epstein-Barr virus (EBV)-transformed human B cell lines was investigated with the aim that this information would lead to detection of similarly aberrant Ig genes In normal human B lymphocytes. Analysis of the productive μ genes in three truncated μ-only human B cell lines showed a consistent structural change where a secondary VH-VHDJH gene rearrangement had occurred. The site of VH-VH joining was suggestive of a V(D)J recombinase-mediated event. A consistent pattern of mutation was also observed In the normal-sized, but non-functional x light chain transcripts, making them incapable of coding for a functional x chain. Using genomlc DNA from peripheral blood lymphocytes of a donor whose B cells were originally used to make one of the truncated μ-only EBV B cell lines, a similarly mutated V, gene was detected and a similar composite VH-VH gene was cloned. The lack of such aberrant VH and Vx genes in non-lymphoid cells of this individual showed that the structural abnormalities In the expressed Ig genes arose somatically during development of that B cell clone. The presence of these altered Ig heavy and light chain genes in the genomic DNA of untransformed lymphocytes also shows that generation of such variant B cell clones can be a pre-neoplastlc event and occurs by genetic mechanisms active during normal B cell development.