GENETIC CONTROL OF CELL GROWTH AND DEVELOPMENT 
Philip Leder, M.D., Senior Investigator 
Cell growth and development are precisely or- 
dered biologic processes under the control of a 
complex genetic program. Dr. Leder and his col- 
leagues have undertaken to understand aspects of 
this program at the molecular genetic level. 
L Genetic Control and Modulation of Oncogenesis. 
A. Nonclassical genetic control of oncogenesis. Cer- 
tain human malignancies tend to be highly prevalent 
in families, leading to the notion that they are con- 
trolled by an array of genes, rather than by a single 
Mendelian locus. Such inheritance patterns are 
called polygenic. Although certain of these genetic 
elements could be classical oncogenes, the nature of 
oncogenesis suggests that tumorigenesis can also be 
influenced by complex features of an organism, such 
as cell population dynamics, host defense mecha- 
nisms, physical barriers to tumor growth and vas- 
cularization, DNA repair mechanisms, and other ge- 
netically controlled processes that are specified by 
polymorphic alleles within human populations. 
Since many malignancies are characterized by the 
specific cell type in which they occur (e.g., Burkitt 
lymphoma occurs in the B cell stage of immunocyte 
development), the genetically programmed devel- 
opmental pathway followed by a cell might also in- 
fluence the occurrence of cancer within that cellu- 
lar lineage. That is, the developmental program 
produces the specific cells "at risk" for malignant 
transformation. Dr. Leder and his colleagues have 
tested this by producing a strain of transgenic mice 
that develop a predictable and reproducible form 
of pre-B cell lymphoma. The pathway of immu- 
nocyte development in this test line was altered by 
breeding into it a transgene from a second strain of 
transgenic mice. The second strain carried a trans- 
gene directing the synthesis of an assembled, mem- 
brane-bound immunoglobulin heavy chain. The net 
effect of introducing the complete immunoglobulin 
heavy-chain transgene is to allow a developing im- 
munocyte to bypass the immunoglobulin gene as- 
sembly stage in B cell development. Bypassing this 
stage of B cell development should reduce or elimi- 
nate the population of developing B cells at the 
cancer-prone stage of their development and thus 
reduce the population of cells at risk. As a conse- 
quence, the immunoglobulin transgene should re- 
duce the incidence of cancer in the test line. 
The immunoglobulin transgene dramatically re- 
duced the incidence of pre-B lymphoma in the test 
strain. In essence, the immunoglobulin transgene 
behaved as an anti-oncogene, but, instead of modu- 
lating transformation at the cellular level, it modu- 
lated cancer incidence at the level of the organism 
by perturbing a developmental pathway. It reduced 
the risk of cancer in the cancer-prone strain. 
B. Antitumor effects of biologic response modifica- 
tion. Dr. Leder's study of complex factors that can 
modulate tumor incidence suggested that specific 
biologic effectors influencing cell differentiation 
could also exert profound effects on carcinogene- 
sis. The cytokines are a group of protein factors 
elaborated by cells that appear to effect cellular 
growth and development. Interleukin-4 (IL-4), one 
of the cytokines described to date, has the ability 
to induce the maturation and class switching of 
B cells). An effort was made to create transgenic 
mice in which the expression of IL-4 was placed 
under the control of immunoglobulin promoter/en- 
hancer sequences, so that its effects on the devel- 
opment of lymphomas could be assessed. Transge- 
nic mice carrying the IL-4 construct exhibited an 
unusual phenotype (currently under investigation) 
that, briefly stated, aborts the development of thy- 
mus-dependent T cells and ultimately proves lethal. 
Because of the effiect of the transgene on the 
developing immune system, another more effec- 
tive means of assessing the antitumor effects of 
cytokines was designed to detect antitumor activity 
that depends on the mobilization of host defenses. 
Malignant cells were transfected to produce (in this 
case) IL-4, and the ability of the transfected, IL-4- 
producing tumor to grow in syngeneic mice was 
measured. The effect of the cytokine could be fur- 
ther assayed by mixing the IL-4 -producing cells 
with nonproducing tumor cells of a variety of ori- 
gins. Dr. Leder and his colleagues were able to 
show that IL-4 has a potent, non-cell-autonomous, 
in vivo antitumor effect. This activity, which is thy- 
mus-independent, appears to be mediated by an in- 
flammatory infiltrate. This result targets IL-4 for fur- 
ther attention as an agent for potential use in the 
treatment of human malignancy. 
II. Transgenic Approach to Embryonic Development. 
Studies in Dr. Leder's laboratory and elsewhere 
have shown the great potential of the transgenic 
mouse system to perturb developmental processes. 
Yet another, and even more instructive, means by 
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