Independent immunoglobulin class-switch events occurring in a single myeloma cell line.

Eckhardt, Laurel A.; Birshtein, Barbara K.

doi:10.1128/mcb.5.4.856

Cited by 79 publications

(52 citation statements)

References 42 publications

(44 reference statements)

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“…The lowered IgH expression of a third class switch mutant, LP1, was also probably the result of changes in posttranscriptional handling of the heavy-chain transcript. While it is formally possible that the IgH transcriptional enhancer (3,15,31) has been deleted in this cell line, loss of the same sequence had no adverse effect on immunoglobulin expression in one and possibly two previously isolated class switch mutants of MPC11 (12,44) or in enhancer deletion mutants of two other cell lines (17,18,41). Furthermore, the Y2a gene transcription rate was not significantly altered in LP1 (Fig.…”

Section: Discussionmentioning

confidence: 86%

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DNA rearrangement causes a high rate of spontaneous mutation at the immunoglobulin heavy-chain locus of a mouse myeloma cell line.

Yu¹,

Eckhardt²

1986

Mol. Cell. Biol.

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The spontaneous mutation rate of immunoglobulin genes expressed in myeloma cells is well above that of other genes expressed in these or in other cell types. The nature of such mutations in one myeloma cell line, MPC11, was explored at the molecular level. Included in this study were MPC11 variants representing 24 independent and spontaneous mutations affecting immunoglobulin secretion. Of the mutants studied, 19 had ceased immunoglobulin heavy chain (IgH) production (nonproducers), and 5 produced from as little as 1/1,000 to as much as 1/10 the amount of immunoglobulin produced by MPC11 (low producers). Only one of the MPC11 mutants (a nonproducer) showed no evidence of DNA rearrangement in or near the expressed IgH gene. The formerly expressed gamma 2b gene had been deleted in 18 of the 19 nonproducers. All of the low producers had undergone DNA rearrangement in or near the expressed IgH gene, and three of them produced immunoglobulin of a new heavy chain class. The cause for reduced heavy-chain synthesis in the low producers is not yet known. However, in several of these mutants, the defect appeared to be posttranscriptional. In these cell lines, steady-state IgH mRNA levels were much lower than in the parent cell line, while the heavy-chain gene transcription rate remained unchanged.

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Section: Discussionmentioning

confidence: 86%

“…To determine whether -y-chain proteins of the normal size were made in the class switch variants, [35 rise to a C-Y2b-C-Y2a "hybrid'" mRNA or protein (or both), as has been seen in a mutagen-induced variant of MPCll (12,14).…”

Section: Resultsmentioning

confidence: 99%

DNA rearrangement causes a high rate of spontaneous mutation at the immunoglobulin heavy-chain locus of a mouse myeloma cell line.

Yu¹,

Eckhardt²

1986

Mol. Cell. Biol.

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“…A number of studies have suggested a preferential role for the 3Ј-IgH enhancer elements in the expression of IgH genes of the class-switched isotypes (37)(38)(39)(40)(41)(42). These observations led us to examine whether there is a link between OCA-B and 3Ј-IgH enhancer element function.…”

Section: Il-4 and Anti-cd40 Stimulation Of The 3ј-igh Enhancer Elemenmentioning

confidence: 99%

Role of OCA-B in 3′-IgH Enhancer Function

Stevens

Ong

Kim

et al. 2000

The Journal of Immunology

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OCA-B (alternately called Bob1 and OBF-1) is a B cell-specific coactivator that interacts with the ubiquitously expressed Oct-1 and the B cell-restricted Oct-2 to activate transcription via the octamer site (5′-ATGCAAAT-3′). OCA-B−/− mice appear to undergo normal Ag-independent B cell maturation. However, Ag-dependent B cell differentiation, including germinal center formation, production of secondary Ig isotypes, and proliferation in response to surface Ig cross-linking, is greatly affected. We demonstrate that the observed reductions in expression of class-switched isotypes in OCA-B−/− mice may be due in part to deficiencies in the function of the 3′-IgH enhancer elements. Furthermore, we find that surface Ig cross-linking represses all the Ig enhancers and that this repression is absent in OCA-B−/− B cells. These results suggest an important role for OCA-B in Ig enhancer function in vivo.

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“…9921 is an IgG2a-producing class switch variant that was derived, through an intermediate, from the IgG2b-producing plasmacytoma MPC11 (24). In the course of the H chain class switch, E was deleted from the ␥2a H chain transcription unit in 9921.…”

Section: Cell Linesmentioning

confidence: 99%

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Zhang

Alaie-Petrillo

Kon

et al. 2007

The Journal of Immunology

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V gene assembly, class switch recombination, and somatic hypermutation are gene-modifying processes essential to the development of an effective Ab response. If inappropriately applied, however, these processes can mediate genetic changes that lead to disease (e.g., lymphoma). A series of control elements within the Ig H chain (Igh) locus has been implicated in regulating these processes as well as in regulating IgH gene transcription. These include the intronic enhancer (Eμ) and several elements at the 3′ end of the locus (hs1,2, hs3a, hs3b, and hs4) known collectively as the 3′ regulatory region. Although it is clear that the Eμ plays a unique role in V gene assembly, it has not been established whether there are unique functions for each element within the 3′ regulatory region. In earlier studies in mice and in mouse cell lines, pairwise deletion of hs3b and hs4 had a dramatic effect on both class switch recombination and IgH gene transcription; deletion of an element almost identical with hs3b (hs3a), however, yielded no discernible phenotype. To test the resulting hypothesis that hs4 is uniquely required for these processes, we induced the deletion of hs4 within a bacterial artificial chromosome transgene designed to closely approximate the 3′ end of the natural Igh locus. When introduced into an Ig-secreting cell line, an Igα transcription unit within the bacterial artificial chromosome was expressed efficiently and the subsequent deletion of hs4 only moderately affected Igα expression. Thus, hs4 does not play a uniquely essential role in the transcription of a productively rearranged Ig VDJCα transcription unit.

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Independent immunoglobulin class-switch events occurring in a single myeloma cell line.

Cited by 79 publications

References 42 publications

DNA rearrangement causes a high rate of spontaneous mutation at the immunoglobulin heavy-chain locus of a mouse myeloma cell line.

DNA rearrangement causes a high rate of spontaneous mutation at the immunoglobulin heavy-chain locus of a mouse myeloma cell line.

Role of OCA-B in 3′-IgH Enhancer Function

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

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