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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2780-2790
RAPID COMMUNICATION
Expression of E2A-HLF Chimeric Protein Induced T-Cell
Apoptosis, B-Cell Maturation Arrest, and Development of Acute
Lymphoblastic Leukemia
Hiroaki Honda,
Toshiya Inaba,
Takahiro Suzuki,
Hideaki Oda,
Yasuhiro Ebihara,
Kohichiro Tsuiji,
Tatsutoshi Nakahata,
Takatoshi Ishikawa,
Yoshio Yazaki, and
Hisamaru Hirai
From the Third Department of Internal Medicine, Faculty of Medicine,
University of Tokyo; the Department of Molecular Biology, Jichi Medical
School, Tochigi-ken; the Department of Pathology, University of Tokyo;
and the Department of Clinical Oncology, Institute of Medical Science,
University of Tokyo, Tokyo, Japan.
The E2A-HLF fusion gene, generated by t(17;19)(q22;p13) in
acute lymphoblastic leukemia (ALL), encodes a chimeric transcription factor in which the trans-activating domains of E2A are
fused to the DNA-binding and dimerization domains of hepatic leukemic factor (HLF). To investigate its biological role, we
generated transgenic mice expressing E2A-HLF using Ig enhancer
and promoter, which direct transgene expression in cells committed to
the lymphoid lineage. The transgenic mice exhibited abnormal
development in the thymus and spleen and were susceptible to infection.
The thymus contained small numbers of thymocytes, and TUNEL staining
showed that higher population of thymocytes were undergoing apoptosis. The spleen exhibited a marked reduction in splenic lymphocytes and the
flow cytometric analyses and the in vitro colony formation assays
showed that the B-cell maturation was blocked at a very early
developmental stage. These findings indicated that the expression of
E2A-HLF induced T-cell apoptosis and B-cell maturation arrest in vivo and that the susceptibility of the transgenic mice to infection
was due to immunodeficiency. Moreover, several transgenic mice
developed acute leukemia, classified as T-ALL based on the surface
marker analysis and DNA rearrangements, suggesting that an additional
event is required for malignant transformation of lymphoid cells
expressing E2A-HLF. Our findings provide insight into the
biological function of E2A-HLF in lymphoid development and also
its role in leukemogenesis.
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