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The AML1/ETO(MTG8) and AML1/Evi-1 Leukemia-Associated Chimeric
Oncoproteins Accumulate PEBP2 (CBF) in the Nucleus More
Efficiently Than Wild-Type AML1
Kozo Tanaka,
Tomoyuki Tanaka,
Mineo Kurokawa,
Yoichi Imai,
Seishi Ogawa,
Kinuko Mitani,
Yoshio Yazaki, and
Hisamaru Hirai
From the Third Department of Internal Medicine and the Department of
Transfusion Medicine and Immunohematology, Faculty of Medicine,
University of Tokyo, Japan.
AML1, a gene on chromosome 21 encoding a transcription
factor, is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22)
chromosomal translocations associated with myelogenous leukemias; as a
result, chimeric proteins AML1/ETO(MTG8) and AML1/Evi-1 are generated, respectively. To clarify the roles of AML1/ETO(MTG8) and AML1/Evi-1 in
leukemogenesis, we investigated subcellular localization of these
chimeric proteins by immunofluorescence labeling and subcellular fractionation of COS-7 cells that express these chimeric proteins. AML1/ETO(MTG8) and AML1/Evi-1 are nuclear proteins, as is wild-type AML1. Polyomavirus enhancer binding protein (PEBP)2 (core binding factor [CBF]), a heterodimerizing partner of AML1 that is located mainly in the cytoplasm, was translocated into the nucleus with dependence on the runt domain of AML1/ETO(MTG8) or AML1/Evi-1 when
coexpressed with these chimeric proteins. When a comparable amount of
wild-type AML1 or the chimeric proteins was coexpressed with
PEBP2(CBF), more of the cells expressing the chimeric proteins showed the nuclear accumulation of PEBP2(CBF), as compared with the cells expressing wild-type AML1. We also showed that the chimeric proteins associate with PEBP2(CBF) more effectively than
wild-type AML1. These data suggest that the chimeric proteins are able
to accumulate PEBP2(CBF) in the nucleus more efficiently than
wild-type AML1, probably because of the higher affinities of the
chimeric proteins for PEBP2(CBF) than that of wild-type AML1.
These effects of the chimeric proteins on the cellular distribution of
PEBP2(CBF) possibly cause the dominant negative properties of the
chimeric proteins over wild-type AML1 and account for one of the
mechanisms through which these chimeric proteins contribute to
leukemogenesis.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1688-1699
© 1998 by The American Society of Hematology.
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