II. Lymphocyte Development. 
Mice carrying the severe combined immunodefi- 
ciency (SCID) mutation lack both mature T and B 
ceils due to an impairment of VDJ recombination. 
Dr. Alt's group characterized this defect in detail by 
analyzing the ability of Abelson murine leukemia 
virus (MLV)- transformed SCID pre-B cells to re- 
arrange endogenous or introduced Ig variable- 
region gene segments. Most pre-B lines derived 
from SCID mice attempt to rearrange endogenous 
heavy-, but not light-chain, variable-region gene 
segments. Such lines express high levels of germ- 
line heavy-chain V transcripts but do not express 
high levels of germline k light-chain transcripts. 
How^ever, Dr. Alt's group derived rare SCID pre-B 
lines that did rearrange endogenous k V gene seg- 
ments, and all transcribed the germline k locus (in 
accord with the accessibility model described 
above). The vast majority of SCID heavy- and light- 
chain coding-sequence joins are grossly aberrant, 
although SCID pre-B lines can form normal coding 
joins at very low frequency— perhaps allowing for 
the "ieakiness" of the SCID mutation. In contrast, 
SCID pre-B cells join the recombination signal se- 
quences flanking germline V gene segments at nor- 
mal efficiency— mechanistically distinguishing cod- 
ing and signal join formation. SCID pre-B lines that 
did not attempt chromosomal coding-sequence 
joining had a relative and selective growth advan- 
tage over those that did; this supports the previous 
suggestion of Dr. Alt's group that the SCID defect 
may lead to unrepaired chromosomal breakage and 
cell death in developing lymphocytes. 
Dr. Alt's group is attempting to utilize SCID mice 
as a model system to create a defined immune sys- 
tem. Transgenic mice carrying functionally assem- 
bled Ig heavy- or light-chain genes in their germline 
have been constructed; the particular heavy- and 
light-chain variable-region genes employed encode 
an antibody of known specificity. Various down- 
stream heavy-chain constant genes have been incor- 
porated into some of these constructs. Individual Ig 
heavy- and light-chain genes have been or currently 
are being introduced into the SCID mice via breed- 
ing with appropriate transgenics. The expectation 
is that germline acquisition of functionally rear- 
ranged Ig heavy- and light-chain genes by SCID 
mice will allow their precursor B cells to bypass the 
SCID defect and generate a monoclonal B cell pop- 
ulation that expresses an antibody of known speci- 
ficity. Transgenic/SCID mice containing functional 
heavy-, light-, or heavy- plus light-chain genes 
should provide a model to study factors involved in 
precursor B cell differentiation as well as elusive 
factors involved in later stages of the immune re- 
sponse, including IgD function and control of so- 
matic mutation. 
III. Regulation of Lymphocyte Differentiation. 
Dr. Alt's group identified a number of novel 
genes involved in lymphocyte differentiation. One 
encodes a myosin regulatory light-chain-like pro- 
tein; this gene is expressed only in Abelson MLV- 
transformed pre-B cells from adult marrow but not 
those from fetal liver. Expression of this gene is 
greatly induced after treatment of normal pre-B 
cells with the pre-B growth factor interleukin-7 
(IL-7). IL-7 treatment of normal pre-B cells causes a 
rapid induction of N-myc proto-oncogene expres- 
sion without a substantial effect on c-myc expres- 
sion. The N-, C-, and L-myc genes encode highly re- 
lated nuclear proteins likely to be involved, at least 
in part, in transcriptional regulation. Differential 
IL-7 induction of N-myc, as opposed to c-myc, in 
pre-B cells supports the suggestion that differential 
expression of myc genes may be involved in pro- 
gression of cells through lymphoid (and other) dif- 
ferentiation pathways. This hypothesis was based 
on the observation that both N- and c-myc are ex- 
pressed in precursor B and T cells, but only c-myc 
is expressed after the stage when these cells ac- 
quire surface receptors. Within the lymphocyte lin- 
eage, L-myc expression was observed only in tu- 
mors representing very immature T cells. 
To further define myc function. Dr. Alt's labora- 
tory is using transgenic and gene-disruption ap- 
proaches. Transgenic mice were used to study de- 
regulated myc gene expression during lymphocyte 
differentiation. When subjugated to dominant Ig 
heavy-chain transcriptional regulatory sequences, 
both N- and L-myc genes caused lymphoid malig- 
nancies. In correspondence to transgene expres- 
sion patterns, N-myc tumors were mostly from 
B lineage cells, whereas L-myc tumors were from 
T lineage cells. B versus T cell-specific expression of 
N- and L-myc transgenes appeared targeted by 
sequences within the corresponding myc genes. 
Transgenic N-myc tumors representing surface 
Ig-positive B cells express some pre-B cell stage- 
specific genes and activities (including VDJ recom- 
binase), possibly due to deregulated N-myc expres- 
sion. To define further the relationship between 
N-myc expression and B cell differentiation. Dr. 
Alt's group developed homologous recombination 
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