Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange

doi:10.1016/0092-8674(84)90047-3

Cell

Volume 36, Issue 4, April 1984, Pages 973-982

https://doi.org/10.1016/0092-8674(84)90047-3 Get rights and content

Abstract

The 15;12 translocations in murine plasmacytomas represent recombination of the myc oncogene with the immunoglobulin C_H locus, often within C_H switch recombination (S_H) regions. Chromosome junctions cloned from four plasmacytomas confirmed that the translocation generates reciprocal C_HS_H-myc and 5′myc-S_H structures. H locus targets included Sα fused to Sμ, Sμ fused to Sγ_2b, and a germline Sα region. The nature of two H locus targets suggests that the target need not be highly active transcriptionally. Switch recombination machinery is implicated in the translocation by the S_H targets and by homology of certain c-myc breakpoints with normal switch recombination sites. Fusion regions revealed deletions, extraneous nucleotides, and one duplication. These results prompt a translocation model in which staggered single-stranded breaks on each chromosome are followed by single-strand excision or polymerization prior to ligation to the other chromosome.

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Chromosomal translocations that join the cellular oncogene Myc (c-myc) with immunoglobulin (Ig) heavy-chain (Igh) or light-chain (Igk, Igl) loci are widely believed to be the crucial initiating oncogenic events in the development of B cell and plasma cell neoplasms in three mammalian species: Burkitt lymphoma (BL) in human beings, plasmacytoma (PCT) in mice, and immunocytoma in rats. Among the Myc–Ig translocations found in these neoplasms, mouse PCT T(12;15)(Igh–Myc) is of special interest because it affords a uniquely useful model system to study the fundamental outstanding questions on the mechanisms, genetics, and biological consequences of Myc translocations. Mouse T(12;15) is the direct counterpart of the human BL t(8;14)(q24;q32) translocation and thus of great relevance for human cancer. Mouse T(12;15) is the only cancer-associated translocation in mice that occurs with high incidence, spontaneity, and cell-type specificity. Due to the development of PCR methods for the detection of the underlying reciprocal Myc–Igh junction fragments, it is now known that mouse T(12;15) can be a dynamic process that begins with the genetic exchange of Myc and the Igh switch μ region (Sμ), progresses by class switch recombination (CSR) just 3′ of the translocation break site, and then undergoes further clonal diversification by micro-deletions in the junction flanks. The molecular pathway that subverts CSR to mediate trans-chromosomal joining of Myc and Sμ (translocation origin) and secondary modification of Myc–Igh junctions (translocation “remodeling”) has not been elucidated, but recent evidence indicates that it includes CSR factors, such as the activation-induced cytidine deaminase (AID), that may also be involved in the ongoing neoplastic progression of the translocation-bearing tumor precursor. Transgenic mouse models of T(12;15)/t(8;14), including newly developed “iMyc” gene-insertion mice, will be useful in elucidating the role of these CSR factors in the progression of Myc-induced B cell tumors.
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Burkitt's lymphoma is invariably associated with chromosomal translocations that juxtapose the c-myc proto-oncogene with regulatory elements of the immunoglobulin heavy (IgH) or light chain loci resulting in the deregulation of c-myc expression. However, the enhancer elements mediating c-myc deregulation in vivo remain largely unidentified. To investigate the role of the IgH 3′-enhancers in c-myc deregulation, we used gene targeting to generate knock-in mice in which four DNase I hypersensitive regions from the murine IgH 3′-region were integrated into the 5′-region of the c-myc locus. The IgH 3′-enhancers induced the up-regulation of c-myc expression specifically in B cells of IgH-3′-E-myc mice. After ∼10 months, the mice developed a Burkitt-like B cell lymphoma with the phenotype of B220⁺, IgM⁺, and IgD^low. Analysis of immunoglobulin gene rearrangements indicated that the lymphoma cells were of clonal origin. The presence of a rapidly expanding population of B cells in the spleen and bone marrow of young knock-in mice at 2–4 months of age was observed. Premalignant splenic B cells of knock-in mice showed higher spontaneous and induced apoptosis; however, malignant B cells were more resistant to apoptosis. The p53-ARF-Mdm2 pathway was disabled in half of the lymphomas examined, in most cases through Mdm2 overexpression. Although c-myc expression was increased in premalignant B cells, the promoter shift from P2 to P1 was observed only in malignant B cells. Our studies demonstrate that the IgH 3′-enhancers play an important role in c-myc deregulation and B cell lymphomagenesis in vivo.
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Bcl-2 translocations in follicular lymphomas (FL) are often associated with downstream immunoglobulin class switch recombination (CSR) on the translocated allele. We studied cell lines with different translocations into the IgH locus to gauge any common features associated with downstream CSR events. CSR associated with chromosomal rearrangements was observed in cells (RL) with translocations similar to those frequently observed in FL (bcl-2-J_H), and such CSR was also seen with a myc (near exon 1)-J_H5 intron translocation (MC116), but not for far 5′-myc-J_H5 intron (P3HR-1) or myc-Sμ translocations (Ramos). Both MC116 and P3HR-1 myc translocations showed evidence for an origin from somatic hypermutation. Therefore, the association of J_H translocations with CSR on the translocated allele is unlikely to be linked with specific translocation mechanisms, and the P3HR-1 configuration indicated that the downstream class switching is not a necessary consequence of (or precondition for) such a translocation event. MC116 and RL, but not P3HR-1 cells, showed constitutive transcription through the translocated IgH alleles, suggesting that transcription through this region or the processing of such transcripts may promote CSR. However, while CSR events clearly occurred in the precursors of MC116 and RL, neither cell line could undergo complete class switching.
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Mature B lymphocytes are able to specifically alter their Ig isotype expression in response to extracellular stimuli via a highly regulated, deletional recombination process called isotype switch recombination. Switch recombination breakpoints predominantly map to large (1–10 kb), G-rich and highly repetitive switch regions that are located directly upstream of immunoglobulin heavy-chain constant region genes. Switch region repeat structures vary considerably both within and between species, but all switch regions contain disproportionate numbers of two pentamer motifs, TGGGN and TGAGC, that are found at or directly adjacent to most analysed switch junctions. We have recently identified an endonuclease activity, Endo-SR, that preferentially cleaves TGGGN and TGAGC switch motifs. We have purified the bovine endonuclease activity to homogeneity and have identified a protein with a molecular weight of ∼ 32 000 that directly correlates with enzyme activity. As discussed in this report, we have found that murine and bovine Endo-SR are preferentially enriched in lymphoid tissue nuclear extracts and that both enzymes demonstrate highly similar physical and biochemical characteristics. However, each enzyme demonstrates related but distinctive specificities for consensus and degenerate TGGGN and TGAGC switch pentamer motifs.
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B lymphocytes can alter selectively their immunoglobulin (Ig) isotype expression by deletional rearrangement of the first active immunoglobulin heavy-chain (IgH) constant region (Cμ) gene with one of six other constant region genes. Recombination breakpoints occur within highly repetitive “switch” (S) regions located upstream of each IgH constant region gene except C_δ. Analysis of rearranged switch DNA junctions has not detected a consensus sequence, although the predominance of two pentamer motifs (TGGGG and TGAGC) at or near these breakpoints and throughout all murine S region sequences has led to their advocacy as the S recombination signals. In this paper, we describe the characterization and partial purification of a lymphoid-specific endonuclease activity which cleaves preferentially murine S region DNA. Enzyme activity selectively produced single- and double-stranded breaks at TGAGC and TGGG motifs within murine Sμ and Sα DNA. Rare cryptic cleavage sites were detected also within non-switch sequences, although cleavage intensities at these sites were reduced greatly, relative to consensus S region cleavages. Analogous activity was found in murine tissue extracts, although among the tissues assayed only spleen and thymus contained detectable activity. Subsequent biochemical characterization of this activity demonstrated that the responsible enzyme (Endo-SR) represented a previously unreported tissue-specific mammalian endonuclease. Endo-SR-specific activity could be enhanced by addition of Mg²⁺ or Ca²⁺ and inhibited by addition of Zn²⁺. Maximal specific activity was detected at pH 5.5 and sharply declined within ±0.5 pH units. In view of this enzyme's sequence- and tissue-specificity, we propose that Endo-SR is a strong candidate for an endonuclease activity associated with the switch recombination process.
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Cell

ArticleTranslocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange

Abstract

Cell

Cell

Cell

Cell

Cell

J. Biol. Chem.

Cell

Cell

J. Mol. Biol.

Cell

Cell

J. Mol. Biol.

Transcriptionally active DNA region that rearranges frequently in murine lymphoid tumors

Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas

Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions

Differential expression of the translocated and the untranslocated c-myc oncogene in Burkitt lymphoma

Science

Screening Xgt recombinant clones by hybridization to single plaques in situ

Science

Sequence of the murine and human cellular myc oncogenes and two models of myc transcription resulting from chromosomal translocation in B lymphoid tumors

EMBO J.

Molecular cloning of translocations involving chromosome 15 and the immunoglobulin Cα gene from chromosome 12 in two murine plasmacytomas

Natural history of the myeloma

Identification and nucleotide sequence of a human locus homologous to the v-myc oncogene of avian myelocytomatosis virus MC29

Nature

Deletions in the constant region locus can account for switches in immunoglobulin heavy chain expression

Nature

Interchromosomal recombination of the cellular oncogene c-myc with the immunoglobulin heavy chain locus in murine plasmacytomas is a reciprocal exchange

EMBO J.

Mouse cmyc oncogene is located on chromosome 15 and translocated to chromosome 12 in plasmacytomas

Science

Article
Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange

Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-J_H fusions