Molecular Genetics of Lymphocyte Development 
and Neoplasia 
Stanley J. Korsmeyer, M.D. — Associate Investigator 
Dr. Korsmeyer is also Professor of Medicine and Molecular Microbiology at Washington University School 
of Medicine, St. Louis. He received his B.S. degree in biology from the University of Illinois, Urbana, and 
his M.D. degree from the University of Illinois, Chicago. He did his internship and residency in internal 
medicine at the University of California, San Francisco, and his postdoctoral research with Thomas 
Waldmann and Philip Leder at NIH, where he became a Senior Investigator at the National Cancer 
Institute. His honors include membership in the American Society for Clinical Investigation. 
GENES that encode receptors for foreign anti- 
gens have provided our most pivotal insights 
into early lymphocyte development and lym- 
phoid malignancies. The genes for immunoglobu- 
lin (Ig), or antibodies, and for the T cell receptor 
(TCR) encode the antigen receptors for B cells 
and T cells, respectively. During early lympho- 
cyte development, recombination at the DNA 
level assembles these genes to create a wide re- 
pertoire of receptor specificities. 
Much of what we know about these genes has 
been gleaned from studies of lymphoid tumors. 
These malignancies are clonal expansions of a 
single cell and provide multiple identical copies 
of these genetic events. Provocatively, the char- 
acteristic interchromosomal translocations that 
typify B cell malignancies break at the Ig genes, 
while those of T cell tumors often occur at the 
chromosomal home of the TCR genes. We have 
exploited this geography to clone the DNA at 
these illegitimate interchromosomal junctures. 
This serves as a bridge from the antigen receptor 
loci to the other chromosomal partner, which has 
often introduced a new cancer-promoting gene. 
As a prototype, we have cloned the juncture 
between chromosomes 1 4 and 1 8 that is present 
in the most frequent form of human lymphoma, 
follicular-type B cell lymphoma. This transloca- 
tion occurs early in the development of a B cell 
and introduces a newly discovered gene, Bel- 2, 
into the Ig locus. A hybrid Bcl-2-lg fusion gene is 
created, resulting in the overproduction of Bcl-2. 
Transgenic mice were created that possess a copy 
of the abnormal Bcl-2-lg fusion gene in their ge- 
netic material. They progressed from an indolent 
expansion of resting B cells to high-grade life- 
threatening lymphomas, recapitulating the natu- 
ral course of the human disease and proving that 
this translocation causes malignancy. The Bcl-2 
protein is unique among proto-oncogenes by be- 
ing located in mitochondria. Moreover, it has a 
novel function in that it blocks the programmed 
death of cells independent of promoting their 
growth. When deregulated, Z?c/- 2 extends the sur- 
vival of cells normally destined to die. Bcl-2 con- 
stitutes the first member of a new oncogene cate- 
gory, regulators of cell death. 
In a parallel set of experiments, unanticipated 
rearrangements into the 6 TCR locus on chromo- 
some 14 have identified the interchromosomal 
translocation sites that typify early T cell acute 
lymphoblastic leukemias. Two of these new 
genes, Ttg-1 from chromosome 11 and Hox-11 
from chromosome 10, are not normally ex- 
pressed in T cells. Instead their function is di- 
verted from their normal sites to T cells. Trans- 
genic mice reveal that redirecting these 
regulatory genes into T cells causes malignancy. 
The majority of chromosomal defects, how- 
ever, have no candidate gene at either side of the 
juncture. The responsible gene lies a consider- 
able distance from known genes. One promising 
approach utilizes portions of chromosomes from 
yeast organisms to obtain and propagate long 
stretches of human DNA. This makes it possible to 
clone and map entire segments of human chro- 
mosomes, precisely linking known genes, and 
generating probes to search for new disease loci. 
This approach has pinpointed the chromoso- 
mal breakpoint and identified a candidate onco- 
gene for an extremely aggressive leukemia of 
childhood. 
This group of studies aims to improve our un- 
derstanding of the genetic pathways of early T 
and B cell development, as well as the aberran- 
cies that result in malignancy. 
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