(Washington University) and his colleagues are con- 
cerned with the proto-oncogenes important in 
lymphocyte development as well as lymphoid ma- 
lignancies. Highly characteristic translocations be- 
tween unrelated chromosomes occur in malignant 
cells of human lymphoma and leukemia. This event 
places putative cancer genes into a new chromo- 
somal environment. One such gene, Bcl-2, isolated 
from human follicular lymphoma, encodes a novel 
mitochondrial protein that represses the pro- 
grammed death of cells. Transgenic mice bearing a 
deregulated Bcl-2 gene in their genetic material in- 
dicate a normal role for Bcl-2 in maintaining im- 
mune responses. Cancer-promoting genes identi- 
fied in T cell tumors represent regulatory genes 
diverted from their normal cell type. Transgenic 
mice that redirect the expression of these genes to 
the thymus prove that they are oncogenic. 
Research performed in the laboratory of Investi- 
gator Owen N. Witte, M.D. (University of California, 
Los Angeles) concerns the interrelated problems of 
blood cell differentiation and cell growth regula- 
tion. This work is focused on two major areas: first, 
developing techniques to grow and manipulate spe- 
cific types of blood cells; and second, investigating 
the function of genes found in human leukemias 
such as Philadelphia chromosome-positive acute 
lymphocytic leukemia and chronic myelogenous 
leukemia. The ABL oncogene is changed by re- 
arrangement in these leukemias, resulting in abnor- 
mal growth regulation and control. Research in 
these areas should ultimately increase knowledge of 
the ways in which oncogene products both regulate 
and stimulate abnormal cell growth, and aid in an 
understanding of the mechanisms that govern nor- 
mal cell growth. 
The complement system consists of a group of in- 
teractive blood and cellular proteins that recognize 
and destroy foreign particles. Components of the 
complement system attach directly to a microbe and 
then promote its destruction by serving as ligands 
for receptors on peripheral blood cells. This process 
must be carefully regulated in order that comple- 
ment components become attached to foreign mate- 
rial and not self-tissue. A goal of the laboratory of 
Investigator John P. Atkinson, M.D. (Washington 
University) is to identify and characterize these regu- 
latory and receptor proteins of the complement sys- 
tem. Special attention has been focused on a multi- 
gene family of functionally, structurally, and 
genetically related, complement regulatory pro- 
teins. These molecules are importantly involved in 
inflammatory processes associated with infections 
and in autoimmune disease states. 
In addition to helping clear and destroy foreign 
proteins such as those of bacteria and viruses, the 
complement system plays a fundamental role in the 
pathogenesis of many human autoimmune diseases, 
including systemic lupus erythematosus and rheu- 
matoid arthritis. The laboratory of Assistant Investi- 
gator V. Michael Holers, M.D. (Washington Univer- 
sity) is analyzing the cell membrane proteins that 
allow the complement system to help regulate the 
immune response and to clear foreign proteins that 
complement has attacked. In addition, they are ana- 
lyzing the roles these proteins play in animal models 
of human autoimmune diseases. The overall goal is 
to further an understanding of the complement sys- 
tem and to learn how to modulate its activities in a 
beneficial manner in autoimmune diseases. 
Lymphocytes are the specific mediators of immu- 
nity. For lymphocytes to respond to infection or 
cancer cells anywhere in the body they must move 
from one part of the body to the next, thus acting 
as an immunosurveillance network. Lymphocytes 
move from one organ to another via their expression 
of homing receptors. The laboratory of Investigator 
Irving L. Weissman, M.D. (Stanford University) has 
identified two kinds of homing receptor molecules 
expressed in lymphocytes that direct their traffic to 
two kinds of lymphoid organs — lymph nodes (the 
swollen glands of infection) and the intestine- 
associated lymphoid organs (tonsils, appendix, and 
Peyer's patches) — and have isolated the genes that 
code for these homing receptors. In addition, they 
have identified one homing receptor that takes lym- 
phocytes to tissues that are infected and/or in- 
flamed. Some lymphocytes that are necessary to 
eliminate cancer cells, virus-infected cells, or 
tissue/organ transplants contain within them mole- 
cules that mediate cell killing. A set of killer mole- 
cules and the genes that encode them have been 
isolated and the molecular mechanisms of cell kill- 
ing are under study. 
The laboratory of Investigator Roger M. Perlmut- 
ter, M.D., Ph.D. (University of Washington) has used 
molecular genetic strategies to examine signal 
transduction mechanisms in hematopoietic cells. By 
expressing novel genes in the lymphocytes of trans- 
genic mice, protein-tyrosine kinases regulating both 
thymocyte maturation and T cell receptor signaling 
have been identified. Signaling pathways that direct 
the appropriate migration of lymphocytes to periph- 
eral immune organs have also been defined. These 
studies serve to illuminate normal signal transduc- 
tion mechanisms and provide model systems that 
should speed development of improved therapies 
for immunological and neoplastic diseases. 
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