The 15;12 chromosome translocation in murine plasmacytomas and the 8;14 in human Burkitt lymphomas often link the cellular myc oncogene to the locus for constant regions of immunoglobulin heavy chains (CH locus). To clarify how and why c‐myc translocation occurs, we have sequenced the mouse and human c‐myc genes and correlated c‐myc transcription with c‐myc rearrangement. Both genes comprise three exons; the second and third encode the myc polypeptide, which is conserved between mammals and birds, particularly in its more basic C‐terminal half. Southern blots showed that four of 12 Burkitt lines have c‐myc linked near CH switch regions and two near the joining region (JH) locus. Hence, immunoglobulin recombination machinery may participate in translocation, although the common myc breakpoint region around exon 1 does not resemble a switch region. Tumours with breakpoints just 5′ to exon 1, or distant from c‐myc, had normal c‐myc mRNAs of 2.25 and 2.4 kb, which differ at their 5′ ends, while tumours with breakpoints within exon 1 or intron 1 had altered c‐myc mRNAs (2.1‐2.7 kb in Burkitt lines), initiated within intron 1. Both types of mRNAs probably yield the same polypeptide. Since the untranslocated c‐myc allele was generally silent, translocation to the CH locus must induce constitutive c‐myc expression. The presence of c‐myc mRNA in immortal but non‐tumorigenic lymphoblastoid cell lines may implicate c‐myc in an immortalization step.

Molecular cloning has recently established that the 15;12 chromosome translocations in murine plasmacytomas fuse DNA from chromosome 15 to the immunoglobulin heavy (H) chain locus, usually within the switch recombination region near the a constant region gene. We show here that the incoming DNA bears the cellular gene (c-myc) homologous to the oncogene (vnmyc) of avian retrovirus MC29. In human Burkitt lymphomas bearing an 8;14 translocation, c-myc was also rearranged, apparently (in at least two cases) to an H chain switch recombination region (IA or a), and both products of a reciprocal chro-

No abstract

The variant (6;15) translocations in murine plasmacytomas join the myc oncogene‐bearing band of chromosome 15 and the immunoglobulin kappa band of chromosome 6. We recently cloned a region from chromosome 15 linked to C kappa and have now used probes from that region to define the major locus of plasmacytoma variant translocations, which we denote pvt‐1. In five of nine plasmacytomas we analysed, the 6;15 translocation resulted from reciprocal recombination between the C kappa locus and a 4.5‐kb region of pvt‐1. Moreover, nearby we located the region shown by others to have undergone a complex (15;12;6) translocation in plasmacytoma PC7183. All the chromosome 6 breakpoints fell between 1 and 3 kb 5′ to C kappa but only two were near J kappa genes. Thus the J kappa ‐C kappa region appears to be a recombination ‘hot spot’ in lymphocytes, but the breaks are unlikely to be mediated via V/J recombination enzymes. Comparison of a cloned 108‐kb region across pvt‐1 and another of 52 kb across c‐myc established that the pvt‐1 breakpoints lie at least 72 kb from the c‐myc promoters. Since c‐myc is expressed at a substantial level, the 6;15 translocation apparently activates c‐myc. Activation may occur directly, at a remarkable distance along the chromosome, or indirectly, via a putative pvt‐1 gene product.

In chronic myeloid leukemia and some cases of acute lymphoblastic leukemia, a 9;22 chromosome translocation has fused most of the c-abl oncogene to a gene designated bcr. To explore in vivo the biological effects of the chimeric gene, we introduced a facsimile of the translocation product, a bcr-v-abl gene, into the mouse germ line under the control of the immunoglobulin heavy-chain enhancer or a retroviral long terminal repeat. Some transgenic mice bearing either construct developed clonal lymphoid tumors. T lymphomas predominated, but some pre-B lymphomas developed. The transgenes were expressed in the tumors but not detectably in the lymphoid tissues of nontumorous transgenic animals, implying that transcription is activated by a low-frequency somatic event. These results demonstrate that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis.

To assess the impact of constitutive N‐myc expression on lymphocytes, we generated lines of transgenic mice bearing the murine N‐myc oncogene coupled to the immunoglobulin heavy chain enhancer (E mu). As in mice carrying an analogous c‐myc construct, E mu‐N‐myc mice exhibit a limited overgrowth of cycling pre‐B cells and eventually succumb to clonal B lymphoid tumours. The endogenous N‐myc and c‐myc alleles are silent in both E mu‐N‐myc and E mu‐myc lymphomas, suggesting that these genes are subject to auto‐ and cross‐regulation. The regulatory interaction and the similar biological effects of N‐myc and c‐myc imply that the two genes perform interchangeable functions in the promotion of cell proliferation.

No abstract

Several mouse and human genes encoding the DNA‐binding homeobox domain are implicated here in haematopoiesis, a differentiation process maintained throughout life. Four homeobox cDNA clones were isolated from bone marrow and spleen of adult mice and two from the human leukaemia cell line K562. They derive from the Hox 1.1, Hox 2.3, Hox 6.1 genes and two previously undescribed genes, one of a type (paired) not found before in vertebrates. A survey of 36 cell lines of the lymphoid, myeloid and erythroid lineages revealed that certain homeobox transcripts were almost ubiquitous, while others were restricted to certain lineages or even particular cell lines. The expression pattern altered in a myeloid and an erythroid line induced to terminal differentiation, and in novel lines that had switched from a lymphoid to a myeloid phenotype. Altogether, the haemopoietic compartment may contain up to 20 homeobox transcripts. In one myeloid leukaemia, DNA rearrangement has perturbed expression. These findings suggest that homeobox genes may influence developmental decisions within the haemopoietic system.