An unusual translocation of immunoglobulin gene segments in variants of the mouse myeloma MPC11

Schnell, Hannelore; Steinmetz, Michael; Zachau, Hans G.; Schechter, Israël

doi:10.1038/286170a0

Cited by 44 publications

(24 citation statements)

References 19 publications

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“…However, as in myeloma T additional DNA fragments of smaller size were found in the DNA of MOPC41 and MOPC21a. No further band could be detected with the J region probe in MOPC321 DNA (this study) or in MPC11 DNA (22). In EcoRI digested DNA of the lambda chain producing myeloma RPC20 two fragments were found which hybridized to the J region probe, indicating that the deletion of the C region on both homologous chromosomes did not include all of the J region C region probe J region probe stricted DNA per slot was analyzed as described in Fig.…”

Section: Resultsmentioning

confidence: 99%

A rearranged DNA sequence possibly related to the translocation of immunoglobulin gene segments

Steinmetz¹,

Altenburger²,

Zachau³

1980

Nucl Acids Res

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A 5.3 kb EcoRI fragment (T3, abbreviations in ref.2) has been cloned from DNA of a kappa light chain producing mouse myeloma. The fragment hybridizes to the 5' flanking sequences of the J1 gene segment but not to C gene sequences of kappa light chain DNA. Restriction nuclease mapping and partial nucleotide sequencing showed that the fragment consists of sequences from the 5' side of the Jl and from the 3' side of a V gene segment, which apparently had been linked in a genomic rearrangement process. These rearranged flanking sequences are not the flanking sequences of the V and J gene segments which had been joined to form the two kappa light chain genes of the myeloma. Fragments with the hybridization properties of T3 have been found also in two other kappa and one lambda chain producing myelomas. The linking of flanking sequences in the myeloma genome is discussed with respect to the mechanism of recombination between V and J gene segments. INTRODUCTIONRearrangement of immunoglobulin light chain gene segments results in the joining of V (variable) and J (joining) gene segments (3,4). Four mechanisms have been proposed for the V-J recombination (5). 1) The copy-insertion model proposes that a V gene segment is duplicated and inserted upstream of a J gene segment.2) The excision-insertion model assumes that the V gene segment itself is excised and then integrated. 3) According to the inversion model a DNA segment is inverted which results in the joining of a V gene segment to a J gene segment in the correct orientation. 4) The deletion model proposes that the DNA segment separating V and J gene segments in germline DNA is deleted in the course of the V-J joining.In sequencing studies with cloned V and J gene fragments a characteristic heptanucleotide sequence was found adjacent to

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Section: Resultsmentioning

confidence: 99%

A rearranged DNA sequence possibly related to the translocation of immunoglobulin gene segments

Steinmetz¹,

Altenburger²,

Zachau³

1980

Nucl Acids Res

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“…3) are consistent with the absence in the RNA of a single coding domain. The occurrence of aberrantly small K mRNAs which encode polypeptides containing only CK and a leader sequence is a frequent occurrence in myelomas and probably normal Bcells (3,35,38,44) and results from a nonproductive VK rearrangement which fails to provide a donor splice site (13,28,42). heavy-chain-positive cell line (18-81A-2) and have shown that they result from transcription of a second VH gene which was nonproductively rearranged in that a termination codon occurred in its D region (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiple immunoglobulin heavy-chain gene transcripts in Abelson murine leukemia virus-transformed lymphoid cell lines.

Alt¹,

Rosenberg²,

Enea³

et al. 1982

Mol. Cell. Biol.

176

128

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Lymphoid cells transformed by Abelson murine leukemia virus (A-MuLV) contain three classes of RNA transcripts from immunoglobulin mu genes. P mu-mRNAs (productive) correspond to the normal 2.7-kilobase (kb) membrane (mu m) and 2.4-kb secreted (mu s) mu mRNA species both in size and coding capacity and occur at approximately equal abundance in most mu-positive (pre-B-like) A-MuLV transformants. A mu-mRNAs (aberrant) generally fall into one of two categories--aberrantly small 2.3-kb mu m and 2.0-kb mu s mRNAs which encode aberrantly small mu polypeptide chains, or normal-sized, V H-containing mu RNAs which do not encode immunologically identifiable mu polypeptide chains. In one case, the latter type of A mu-mRNA was demonstrated to result from an in-phase termination codon in the D segment of the mu mRNA. Also, most, if not all, A-MuLV transformants express members of a 3.0 to 1.9-kb set of C mu-containing, but V H-negative S mu-RNAs (for sterile), the expression of which may occur simultaneously with but independently of P mu-mRNAs or A mu-mRNAs. The S mu-RNA sequences do not encode immunologically identifiable mu chains and can be produced by cells with unrearranged heavy-chain alleles, such as T-lymphocytes, although the structure of the S mu-RNAs from T-lymphoid cells appears to be different from that of B-lymphoid cell S mu-RNAs. Certain A-MuLV transformants also express gamma-RNA sequences that are probably analogous to the three different forms of mu RNA. These data support the concept that heavy-chain allelic exclusion, like that of light chains, is not mediated by control at the DNA or RNA levels but is probably a consequence of feedback control from cytoplasmic mu chains.

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“…Cloning and sequencing of the gene have revealed that an aberrant rearrangement removed the J segment and its 5' consensus splice sequence. When the precursor transcript is spliced, the entire V region is deleted (8,43,44). The resulting mRNA codes for the leader peptide and kappa constant region sequences (25).…”

Section: Discussionmentioning

confidence: 99%

Loss of a consensus splice signal in a mutant immunoglobulin gene eliminates the CH1 domain exon from the mRNA.

Brandt

Morrison

Birshtein³

et al. 1984

Mol. Cell. Biol.

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A series of mouse myeloma mutants, derived from a cell line of the murine MPC-11 tumor (y2b, kappa), resemble human heavy-chain disease in their loss of an internal domain (exon). In these mutants, most of the -y2b CH, exon was present in the nuclear RNA but was removed during splicing to form the mature cytoplasmic RNA. Amino acid sequence studies of one mutant (10.1) are consistent with the loss of the complete CH, domain. A second mutant cell line (I17) derived from 10.1 and containing the same CH, alteration was shown by Si nuclease protection experiments to have an additional mRNA deletion spanning the CH_-CH3 domain boundary. This second deletion was shown to result from a genomic alteration that provided a marker for the isolation of the expressed H-chain allele. To determine the basis of the CH, splicing defect, the 117 genomeexpressed y2b constant region DNA was cloned. Sequence studies showed a deletion of 99 nucleotides around the 3' end of the CH, domain, which removed the splice site and flanking DNA, apparently causing the aberrant splicing of the RNA transcript. The sequence deleted in the mutant is flanked by short repeats of the octameric sequence CCAGCCAG in the wild-type gene. In the mutant, one copy of the repeat, in addition to the sequences between the repeats, has been lost.Many eucaryotic genes have been found to contain intervening sequences (IVSs) which interrupt coding regions. The IVSs are transcribed with the coding sequences and are removed by splicing to generate mature functional RNA. Splicing has been shown to be important for regulation of gene expression in many cases (12). The study of splicing mutants will be important in elucidating the mechanism of splicing and how it is controlled. Some mutants with DNA alterations consistent with errors in splicing have recently been described (16,17,22,23,31,37,38). In this communication, we describe experiments showing that a series of immunoglobulin heavy-chain deletion mutants exhibit altered processing of the nuclear precursor RNA. These mouse myeloma mutants share some features with human heavy-chain disease.Several human heavy-chain disease proteins have been shown to have internal deletions beginning or ending near the hinge (20,21). The molecular explanation for these altered proteins remains obscure since the DNA and parental cell from which they arose are not available for study; altered RNA splicing may explain the origin of some. The myeloma cell culture system is well suited for elucidating the mechanisms by which mutants in immunoglobulin production arise and for generating mutants in gene expression. The mutation frequency in the immunoglobulin genes is high (1, 10); mutants can be readily identified and isolated (9). Parents and progeny can be compared directly to localize significant DNA alterations.We have previously described the mRNA and proteins produced in a series of myeloma mutants derived from the MPC-11 cell line 45.6. Mutant 10.1 arose spontaneously from 45.6 and synthesizes a y2b heavy chain with a deletion of...

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An unusual translocation of immunoglobulin gene segments in variants of the mouse myeloma MPC11

Cited by 44 publications

References 19 publications

A rearranged DNA sequence possibly related to the translocation of immunoglobulin gene segments

A rearranged DNA sequence possibly related to the translocation of immunoglobulin gene segments

Multiple immunoglobulin heavy-chain gene transcripts in Abelson murine leukemia virus-transformed lymphoid cell lines.

Loss of a consensus splice signal in a mutant immunoglobulin gene eliminates the CH1 domain exon from the mRNA.

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