Following the Life History of Lymphocytes 
Irving L. Weissman, M.D. — Investigator 
Dr. Weissman is also the Karel andAvice Beekhuis Professor of Cancer Biology and Professor of Pathology, 
Developmental Biology, and (by courtesy) Biology at Stanford University School of Medicine. He directs 
the Program for Molecular and Genetic Medicine and the Immunology Program. He received his M.D. 
degree from Stanford and remained to do postdoctoral studies in the Department of Radiology. He also 
studied at Oxford with Jim Gowans in 1964 and returned in 1975 for part of a sabbatical year, which he 
then completed with Melvin Cohn at the Salk Institute. Dr. Weissman is a member of the National Acad- 
emy of Sciences and the American Academy of Arts and Sciences. 
LIKE all other blood cells, lymphocytes — the 
principal players in immune recognition of 
self from nonself — are derived ultimately from 
stem cells in the bone marrow. It is both biologi- 
cally and clinically important to delineate the de- 
cisions these bone marrow precursors make as 
they pass through microenvironments that define 
the type of lymphocyte (or other blood cell) they 
shall become. We have focused on identifying the 
earliest cell in the bone marrow that has multipo- 
tent capacity. 
Three years ago we were able to isolate the he- 
matopoietic stem cell of the mouse. This past 
year we demonstrated its full developmental po- 
tential by transferring a single stem cell from one 
strain mixed with 100 stem cells from another 
strain of mouse into lethally irradiated mice of 
the second strain. Remarkably, in a significant 
fraction of animals, the stem cells gave rise to 
blood cells and tissue lymphocytes. In every case 
where donor-strain cells were found, all blood 
cell types had come from the single marked cell. 
In one-third of these cases, the stem cell prolif- 
erated; very large numbers of daughter blood 
cells were generated through the life of the ani- 
mal. In these mice, thousands of stem cells, de- 
rived from the initially injected single cell, could 
be retrieved and transferred to a second genera- 
tion of irradiated animals, all of whom were fully 
reconstituted. Thus this stem cell has a remark- 
able profile of activities, including that of mas- 
sive self-renewal. 
In the past year we have traced how one of the 
first daughter cells from the stem cell — the pre- 
B lymphocyte in bone marrow — becomes leuke- 
mic. This work was supported jointly by the Na- 
tional Cancer Institute of the National Institutes 
of Health and the Howard Hughes Medical Insti- 
tute. It had its origin several years ago when my 
laboratory — and independently that of another 
HHMI investigator. Max Cooper (University of 
Alabama at Birmingham) — identified a molecule 
present at low levels on normal pre-B lympho- 
cytes and at much higher levels in leukemias and 
lymphomas of the pre-B series. We called the mol- 
ecule the 6C3/BP-1 antigen, here abbreviated Ag 
(to signify antigen) . 
Like hematopoietic stem cells, pre-B cells are 
dependent for their growth on a class of stromal 
cells found embedded inside bone cavities — the 
bone marrow. We had cloned the particular bone 
marrow stromal cells that support normal pre-B 
lymphocytes and had found that they provide a 
good culture microenvironment in which to 
study the process whereby Abelson leukemia 
virus causes pre-B cells to become leukemias 
and/or lymphomas. Among the products of these 
stromal cells is the protein growth factor inter- 
leukin-7 (IL-7) . Normal pre-B cells don't express 
IL-7, while the stromal cells that support the 
growth of these normal and preneoplastic pre-B 
cells do. 
The Ag is only expressed at high levels on these 
leukemias and lymphomas at a late stage of the 
neoplastic development in a test tube containing 
stromal cells, pre-B target cells, and the leuke- 
mia virus. We were therefore interested in deter- 
mining whether the conversion from stromal cell 
dependence to stromal cell-independent malig- 
nant growth resulted from tumor cell expression 
of IL-7. In fact, every Abelson leukemia virus- 
induced pre-B leukemia expressed the growth 
factor. More importantly, by specifically block- 
ing the expression of IL-7, we could prevent the 
growth of these leukemias in tissue culture. 
Thus we have demonstrated what we think is a 
critical step in the passage from normal cell to 
leukemic cell — the expression of a growth factor 
for which the tumor cell had a receptor. This 
result confirms in part a hypothesis we pro- 
posed over 15 years ago: receptor-mediated 
leukemogenesis. 
We next investigated whether the high-level 
expression of the Ag might have some signifi- 
cance for the growth of tumor cells in vitro or in 
vivo. Our collaboration with Max Cooper 
brought some striking insights to this problem. 
His group had cloned the cDNA encoding the Ag 
and had found it to contain sequences in common 
with aminopeptidase A, a metalloproteinase. 
467 
