C-myc Gene Rearrangement Research Articles

Frequent c-myc oncogene activation and infrequent presence of Epstein- Barr virus genome in AIDS-associated lymphoma

Sixteen cases of histologic intermediate-grade and high-grade AIDS-associated non-Hodgkin's lymphoma (NHL) were studied for the presence and patterns of c-myc gene and bcl-2 locus rearrangements. The presence of Epstein-Barr virus (EBV) sequences and proteins and HTLV-I sequences were also investigated. c-myc gene rearrangements analogous to those observed in sporadic Burkitt lymphomas were detected in 12 of 16 cases. Six of 16 cases had detectable EBV sequences and proteins. None of the cases displayed bcl-2 rearrangements or contained HTLV-I sequences. These data suggest a frequent role for c-myc activation in the pathogenesis of AIDS-associated NHL, independent of histologic type. Conversely, EBV does not appear to be directly involved in lymphomagenesis in the majority of AIDS-associated NHLs.

Frequent c-myc Oncogene Activation and Infrequent Presence of Epstein-Barr Virus Genome in AIDS-Associated Lymphoma

Abstract Sixteen cases of histologic intermediate-grade and high-grade AIDS- associated non-Hodgkin's lymphoma (NHL) were studied for the presence and patterns of c-myc gene and bcl-2 locus rearrangements. The presence of Epstein-Barr virus (EBV) sequences and proteins and HTLV-I sequences were also investigated. c-myc gene rearrangements analogous to those observed in sporadic Burkitt lymphomas were detected in 12 of 16 cases. Six of 16 cases had detectable EBV sequences and proteins. None of the cases displayed bcl-2 rearrangements or contained HTLV-I sequences. These data suggest a frequent role for c-myc activation in the pathogenesis of AIDS-associated NHL, independent of histologic type. Conversely, EBV does not appear to be directly involved in lymphomagenesis in the majority of AIDS-associated NHLs.

Structural abnormality and over-expression of the myc gene in feline leukemias.

Tumor cells of feline leukemia were examined for structural abnormality and expression of the myc gene. Four of 12 spontaneous leukemia cases showed structural abnormalities of the myc gene detected by Southern blotting analysis. Of these 4 cases, one (Case 1) showed a DNA rearrangement in the 5' portion of the c-myc locus associated with integration of feline leukemia virus (FeLV) genome. Another case had a newly inserted myc gene which was transduced by FeLV. In the 2 other cases, no relation of abnormalities of the myc gene to FeLV was detected. One case of experimental leukemia induced by inoculation of a cell line, FT-1, established from Case 1 showed a c-myc gene rearrangement similar to that observed in Case 1. Expression of myc RNA was examined in 3 leukemia T-cell lines, FT-1, FL74 and F422, by Northern blotting analysis. A high level of myc transcript was detected in all 3 cell lines. The size of myc RNAs in FT-1 and FL74 was the same as that of normal myc RNA, while in F422 which had myc-containing FeLV (myc-FelV), the full genome and spliced form of myc-FeLV viral RNA were detected.

Presence of a c-myc transcript initiated in intron 1 in Friend erythroleukemia cells and in other murine cell types with no evidence of c-myc gene rearrangement.

In Friend murine erythroleukemia cells, although no detectable c-myc gene rearrangement was found, we observed, in addition to the normal 2.3-kilobase c-myc transcript, the presence of a 2.3-kilobase c-myc mRNA initiated in intron 1 at a promoter site called P3. The intron 1-initiated transcript has a longer half-life than the normal c-myc mRNA. This c-myc transcript initiated in intron 1 was also found in other murine cell types where no rearrangement of the c-myc locus has been reported.

Presence of a c-myc transcript initiated in intron 1 in Friend erythroleukemia cells and in other murine cell types with no evidence of c-myc gene rearrangement.

In Friend murine erythroleukemia cells, although no detectable c-myc gene rearrangement was found, we observed, in addition to the normal 2.3-kilobase c-myc transcript, the presence of a 2.3-kilobase c-myc mRNA initiated in intron 1 at a promoter site called P3. The intron 1-initiated transcript has a longer half-life than the normal c-myc mRNA. This c-myc transcript initiated in intron 1 was also found in other murine cell types where no rearrangement of the c-myc locus has been reported.

Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis.

AIDS (acquired immune deficiency syndrome) and ARC (AIDS-related complex) are associated with a spectrum of lymphoproliferative disorders ranging from lymphadenopathy syndrome (LAS), an apparently benign polyclonal lymphoid hyperplasia, to B cell non-Hodgkin's lymphoma (B-NHL), i.e., malignant, presumably monoclonal B cell proliferations. To gain insight into the process of lymphomagenesis in AIDS and to investigate a possible pathogenetic relationship between LAS and NHL, we investigated the clonality of the B or T lymphoid populations by Ig or T beta gene rearrangement analysis, the presence of rearrangements involving the c-myc oncogene locus, and the presence of human immunodeficiency virus (HIV) sequences in both LAS and B-NHL biopsies. Our data indicate that multiple clonal B cell expansions are present in a significant percentage of LAS (approximately 20%) and B-NHL (60%) biopsies. c-myc rearrangements/translocations are detectable in 9 of our 10 NHLs, but not in any of the LAS cases. However, only one of the B cell clones, identified by Ig gene rearrangements carries a c-myc gene rearrangement, suggesting that only one clone carries the genetic abnormality associated with malignant B cell lymphoma. Furthermore, the frequency of detection of c-myc rearrangements in AIDS-associated NHLs of both Burkitt and non-Burkitt type suggest that the biological alterations present in AIDS favor the development of lymphomas carrying activated c-myc oncogenes. Finally, our data show that HIV DNA sequences are not detectable in LAS nor in NHL B cell clones, suggesting that HIV does not play a direct role in NHL development. Taken together, these observations suggest a model of multistep lymphomagenesis in AIDS in which LAS would represent a predisposing condition to NHL. Immunosuppression and EBV infection present in LAS can favor the expansion of B cell clones, which in turn may increase the probability of occurrence of c-myc rearrangements leading to malignant transformation.

Gene localization on sorted chromosomes: definitive evidence on the relative positioning of genes participating in the mouse plasmacytoma-associated typical translocation.

Experiments have been carried out to establish the relative position of the mouse Ig heavy chain locus and the c-myc oncogene. In mouse plasmacytoma with the typical rcpt(12;15) chromosome translocation the c-myc oncogene is juxtaposed to one of the heavy chain genes in a head-to-head orientation. Since the relative orientations of the c-myc locus and the Ig heavy chain gene cluster on the corresponding mouse chromosomes had not been settled, it was not known whether the rearranged c-myc gene is transposed to chromosome 12 or remains on chromosome 15. To decide which of the two alternatives is correct, we separated the translocation chromosomes by fluorescence-activated chromosome sorting. The separated chromosomal fractions were hybridized with myc-specific DNA probes corresponding to the first or second/third exons in a chromosome spot assay. The results presented here indicate that the c-myc gene in mouse plasmacytoma carrying the typical translocation, as in the human Burkitt lymphoma analogous translocation, transposes to the chromosome carrying the Ig heavy chain locus. These results also establish the orientations of the Ig heavy chain locus and the c-myc locus on their normal chromosomes.

Hemizygous interstitial deletion of chromosome 15 (band D) in three translocation-negative murine plasmacytomas.

Three murine plasmacytomas that were exceptional in lacking the characteristic (12;15) or (6;15) translocations were studied by G banding and high-resolution banding. One of every two chromosomes 15 (two of four in tetraploid tumors) was shortened in all three tumors. High-resolution banding analysis revealed that this was due to an interstitial deletion in the 15D band region. The two breaks responsible for the deletion have been tentatively localized to the interface of bands D2/3' and within band D2. One of the three plasmacytomas, ABPC45, had a rearranged c-myc gene. All three tumors contained a greater abundance of 2.4-kilobase myc RNA transcripts than normal spleen or thymus. The c-myc gene is located in the 15 D2/3 band region. We suggest that it may have joined the centromeric portion in the deletion plasmacytomas. This transposition may have led to its constitutive activation, as in the more frequent translocation-carrying plasmacytomas.

A novel 6:10 chromosomal translocation in the murine plasmacytoma NS-1.

Specific chromosomal abnormalities are regularly associated with many murine and human malignancies. In particular, the majority of murine plasmacytomas and human Burkitt's lymphomas contain a characteristic translocation which results in the juxtaposition of a cellular oncogene, c-myc, with the immunoglobulin heavy-chain gene locus, and this rearranged c-myc directs the synthesis of qualitatively and quantitatively abnormal transcripts which may have an aetiological role in the development of the transformed state in lymphoid malignancies. Similarly, rearrangement and abnormal expression of c-myb (ref. 10) and c-mos (ref. 11) has been reported in other murine lymphoid tumours. Here we describe a novel 6:10 chromosomal translocation in the murine plasmacytoma cell line NS-1 which juxtaposes the immunoglobulin Ck gene with a single-copy sequence of unknown function. The NS-1 plasmacytoma is a frequently used fusion partner in hybridoma production and is known to contain a rearranged c-myc gene and a genetic element which transforms normal mouse fibroblasts in DNA-mediated transfection assays. We conclude that individual B-cell tumours may contain multiple chromosomal translocations perhaps relevant to oncogenesis.

Products of a reciprocal chromosome translocation involving the c-myc gene in a murine plasmacytoma.

The structures of the rearranged c-myc gene products derived from a rcp T(12;15) have been investigated in the MPC-11 (IgG2b kappa) plasmacytoma. The rcp T(12;15) in MPC-11 is a reciprocal exchange between the c-myc gene on chromosome 15 and the immunoglobulin gamma 2a switch region (S gamma 2a) on chromosome 12. The c-myc gene is broken within a 5'-nontranslated exon, thereby separating the promoter region of the normal c-myc gene from its protein coding sequences. This reciprocal rearrangement results in the loss of 11 base pairs of c-myc sequence and 300 base pairs of S gamma 2a sequence at the point of recombination. Sequences that represent the promoter region of the normal c-myc gene are present in the 5'-myc reciprocal fragment. A comparison of the nucleotide sequences at the recombination site of a number of c-myc rearrangements reveals a common feature that may have mechanistic importance for these translocation events.

Translocations among antibody genes in human cancer.

The characteristic chromosomal translocations that occur in certain human malignancies offer opportunities to understand how two gene systems can affect one another when they are accidentally juxtaposed. In the case of Burkitt lymphoma, such a translocation joins the cellular oncogene, c-myc, to a region encoding one of the immunoglobulin genes. In at least one example, the coding sequence of the rearranged c-myc gene is identical to that of the normal gene, implying that the gene must be quantitatively, rather than qualitatively, altered in its expression if it is to play a role in transformation. One might expect to find the rearranged c-myc gene in a configuration that would allow it to take advantage of one of the known immunoglobulin promoters or enhancer elements. However, the rearranged c-myc gene is often placed so that it can utilize neither of these structures. Since the level of c-myc messenger RNA is often elevated in Burkitt cells, the translocation may lead to a deregulation of the c-myc gene. Further, since the normal allele in a Burkitt cell is often transcriptionally silent in the presence of a rearranged allele, a model for c-myc regulation is suggested that involves a trans-acting negative control element that might use as its target a highly conserved portion of the c-myc gene encoding two discrete transcriptional promoters.

The human c-myc oncogene: Structural consequences of translocation into the igh locus in Burkitt lymphoma

We have determined the- sequence of the normal human c-myc gene and compared it to portions of a c-myc gene that has been translocated into the immunoglobulin heavy chain locus in a Burkitt lymphoma cell. The normal c-myc gene is encoded in three discrete exons divided by two large intervening sequences. Its mRNA is transcribed from two active promoters located about 150 nucleotides from one another. Each promoter initiates transcription of a long (∼550 bp) untranslatable leader sequence encoding the entire first axon. This axon and additional 5′ flanking sequences are tightly conserved between mouse and man. In the Burkitt cell BL22, the rearranged c-myc gene retains both promoters and is unchanged in its amino acid coding domains. Translocation of this gene joins it to the immunoglobulin heavy chain switch region at a point approximately 1000 by 5′ to the dual c-myc promoters. These genes are joined in opposite transcriptional orientation. The structure of the translocated gene and the nature of its linkage to the immunoglobulin locus and the presence of two c-myc promoters and consequently two long leader sequences raise novel possibilities for the activation of an oncogene.