The myc family of cellular oncogenes contains three known members. The N-myc and c-myc genes have 5'-noncoding exons, strikingly homologous coding regions, and display similar oncogenic potential in an in vitro transformation assay. The L-myc gene is less well characterized, but shows homology to N-myc and c-myc (ref. 6; also see below). c-myc is expressed in most dividing cells, and deregulated expression of this gene has been implicated in the development of many classes of tumours. In contrast, expression of N-myc has been found only in a restricted set of tumours, most of which show neural characteristics; these include human neuroblastoma, retinoblastoma and small cell lung carcinoma (SCLC). L-myc expression has so far been found only in SCLC. Activated N-myc and L-myc expression has been implicated in oncogenesis; for example, although N-myc expression has been found in all neuroblastomas tested, activated (greatly increased) N-myc expression, resulting from gene amplification, is correlated with progression of the tumour. We now report that high-level expression of N- and L-myc is very restricted with respect to tissue and stage in the developing mouse, while that of c-myc is more generalized. Furthermore, we demonstrate that N-myc is not simply a neuroectoderm-specific gene; both N- and L-myc seem to be involved in the early stages of multiple differentiation pathways. Our findings suggest that differential myc gene expression has a role in mammalian development and that the normal expression patterns of these genes generally predict the types of tumours in which they are expressed or activated.

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Previous work (6-10) has shown that allelic exclusion of Ig gene expression is controlled by functionally rearranged mu and kappa genes. This report deals with the comparison of membrane mu (micron) and secreted mu (microsecond) in promoting such feedback inhibition. Splenic B cell hybridomas were analyzed from transgenic mice harboring a rearranged kappa gene alone or in combination with either an intact rearranged mu gene or a truncated version of the mu gene. The intact mu gene is capable of producing both membrane and secreted forms of the protein, while the truncated version can only encode the secreted form. The role of the microsecond was also tested in pre-B cell lines. Analysis of the extent of endogenous Ig gene rearrangement revealed that (a) the production of micron together with kappa can terminate Ig gene rearrangement; (b) microsecond with kappa does not have this feedback effect; (c) microsecond may interfere with the effect of micron and kappa; and (d) the feedback shown here probably represents a complete shutoff of the specific recombinase by micron + kappa; the data do not address the question of mu alone affecting the accessibility of H genes for rearrangement.

The ability to engraft human PBMC or fetal tissue immune cells in the severe combined immunodeficient (SCID) mouse has created a need for characterization of these systems and their application to disease models. We demonstrate that SCID mice reconstituted with PBMC support the growth and differentiation of a restricted set of B cells. Human IgG levels of 1-2 mg/ml (10-20% of normal human serum levels) were routinely achieved in spite of a serum half life of only 12 d. Ig levels peaked around 50 d and Ig production was maintained for > 100 d. The Ig was > 85% IgG though some IgM, IgA, IgD, and even IgE could be detected. However, the human IgG produced in hu-PBL-SCID mice was pauci-clonal when analyzed by isoelectric focusing and by kappa/lambda light chain usage. Using a new polymerase chain reaction based analysis capable of monitoring individual VH family utilization, we found that the engrafted B cells showed skewed and restricted human VH subfamily utilization. These parameters were markedly variable among hu-PBL-SCID mice reconstituted from the same donor cell population at both early (21-50 d) and late stages (> 100 d). Hu-PBL/CVI-SCID mice constructed with cells from patients with common variable immunodeficiency with an in vitro block in terminal B cell differentiation produced human Ig responses that were quantitatively the same as those produced by hu-PBL-SCID mice from normal donors. The hu-PBL-SCID system using PBMC appears to lead to growth and Ig production by a small number of B