Mol Cell Biol, February 1998, p. 846-858, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Radiobiology Division,
Received 18 August 1997/Returned for modification 6 October
1997/Accepted 9 November 1997
The AML1-CBF
transcription factor complex is essential for the
definitive hematopoiesis of all lineages and is the most frequent target of chromosomal rearrangements in human leukemia. In the t(8;21)
translocation associated with acute myeloid leukemia (AML), the
AML1(CBFA2/PEBP2
B) gene is juxtaposed to the
MTG8(ETO/CDR) gene. We show here that the
resultant AML1-MTG8 gene product specifically and strongly interacts
with an 85-kDa phosphoprotein. Molecular cloning of cDNA indicated that
the AML1-MTG8-binding protein (MTGR1) is highly related to MTG8 and
similar to Drosophila Nervy. Comparison of amino acid
sequences among MTGR1, MTG8, and Nervy revealed four evolutionarily
conserved regions (NHR1 to NHR4). Ectopic expression of AML1-MTG8 in
L-G murine myeloid progenitor cells inhibits differentiation to mature
neutrophils and induces cell proliferation in response to granulocyte
colony-stimulating factor (G-CSF). Analysis with C-terminal deletion
mutants of AML1-MTG8 indicated that the region of 51 residues (488 to
538), which contains NHR2, is essential for the induction of
G-CSF-dependent cell proliferation. Immunoprecipitation analysis
indicates that this region is required for AML1-MTG8 to form a stable
complex with MTGR1. Overexpression of MTGR1 stimulates AML1-MTG8 to
induce G-CSF-dependent proliferation of L-G cells and to interfere with
AML1-dependent transcription. These results suggest that AML1-MTG8
could function as a complex with MTGR1 and that the complex might be
important in promoting leukemogenesis.
*
Corresponding author. Mailing address: Radiobiology
Division, National Cancer Center Research Institute, 5-1-1 Tsukiji,
Chuo-ku, Tokyo 104, Japan. Phone: 81-3-3542-2511, ext. 4751. Fax:
81-3-3542-0688. E-mail: ikitabay{at}ncc.go.jp.
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