population of thymocytes representing an immature 
CD4~8^ intermediate stage is preferentially af- 
fected. This model indicates that aberrant expres- 
sion of putative transcription factors plays a primary 
role in the genesis of T cell acute lymphocytic leu- 
kemia (ALL). 
HOXl i is a novel homeobox discovered in T cell 
ALL at the site of the t(10;l4).In normal tissues it is 
expressed in embryonic brain but is not avidly ex- 
pressed in thymus or in resting or activated T cells. 
Some lines of transgenic mice that overexpress 
HOXl 1 in thymus show perturbed T cell develop- 
ment. Total thymocytes are reduced to <10/6, with 
marked diminution in CD4"'"8* double-positive and 
single-positive cells. The S phase percent is normal 
in immature CD3~ thymocytes, but is markedly in- 
creased to 30% with maturation. 
Transgenic thymocytes demonstrate accelerated 
apoptosis. To date, 33% (9/27) of transgenic mice 
with an abnormal phenotype developed T cell lym- 
phoma, while none (0/64) with a normal pheno- 
type developed lymphoma. The mice provide a 
model to dissect the role of altered cell cycle pro- 
gression and programmed cell death in oncogenesis. 
The t(4;ll) Breakpoint Found 
in Aggressive ALL Generates a Novel 
Fusion Transcript 
Chromosome segment llq23, a common break- 
point in mixed-lineage leukemias, includes the 
t(4;ll) of preB/monocytic ALL. As these break- 
points were distant from known genes, yeast artifi- 
cial chromosome (YAC) technology was employed. 
A 280-kb YAC of llq23 origin was characterized 
and shown to span the breakpoints. Topoisomerase 
Il-binding sites and x like sequences were noted 
near the breakpoint, suggesting a role for these ele- 
ments in the translocation. 
Leukemias bearing a t(4;ll) demonstrate an ab- 
normal-sized transcript. Fusion cDNAs from the 
der(ll) predict a chimeric protein composed of 
centromeric 5' sequences from llq23 and telo- 
meric 3' sequences from 4q2 1 . The juxtaposition of 
two newly discovered genes creates a fusion protein 
novel to these poor-prognosis leukemias. 
Dr. Korsmeyer is also Professor of Medicine and 
Molecular Microbiology at Washington Univer- 
sity School of Medicine and Physician at Barnes 
Hospital, St. Louis. 
Articles 
Korsmeyer, S.J. 1992. Bcl-2: an antidote to pro- 
grammed cell death. Cancer Surv 15:1-12. 
Korsmeyer, S.J. 1992. Bcl-2 initiates a new cate- 
gory of oncogenes: regulators of cell death. Blood 
80:879-886. 
Korsmeyer, S.J. 1992. Bcl-2: a repressor of lym- 
phocyte death. Immunol Today 13:285-288. 
Korsmeyer, S.J. 1992. Chromosomal transloca- 
tions in lymphoid malignancies reveal novel 
proto-oncogenes. Annu Rev Immunol 10:785- 
807. 
McGuire, E.A., Rintoul, C.E., Sclar, G.M., and Kors- 
meyer, S.J. 1992. Thymic overexpresion of Ttg- 1 
in transgenic mice results in T-cell acute lympho- 
blastic leukemia/lymphoma. Mol Cell Biol 12: 
4186-4196. 
Nunez, G., Hockenbery, D., McDonnell, TJ., Soren- 
sen, CM., and Korsmeyer, S.J. 1991- Bcl-2 
maintains B cell memory. Nature 353:71-73. 
Rao, L., Debbas, M., Sabbatini, P., Hockenbery, D., 
Korsmeyer, S.J., and White, E. 1992. The adeno- 
virus ElA proteins induce apoptosis, which is in- 
hibited by the ElB 19-kDa and Bcl-2 proteins. 
Proc Natl Acad Sci USA 89:7742-7746. 
Sentman, C.L., Shutter, J.R., Hockenbery, D., 
Kanagawa, O., and Korsmeyer, S.J. 1991. bcl-2 
inhibits multiple forms of apoptosis but not nega- 
tive selection in thymocytes. Cell 67:879-888. 
Yeh, T.-M., Korsmeyer, S.J., and Teale, J.M. 1991. 
Skewed B cell family repertoire in Bcl-2-Ig 
transgenic mice. Int Immunol 3:1329-1333- 
IMMUNOLOGY 3 4 3 
