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Prepublished online as a Blood First Edition Paper on June 19, 2003; DOI 10.1182/blood-2002-12-3944.
Submitted January 2, 2003
Accepted June 8, 2003
A novel EVI1 gene family, MEL1 lacking a PR domain (MEL1S) is mainly expressed in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation
Ichiro Nishikata, Hidenori Sasaki, Mutsunori Iga, Yoko Tateno, Suzuko Imayoshi, Norio Asoh, Takuro Nakamura, and Kazuhiro Morishita*
Department of Biochemistry, Miyazaki Medical College, Kiyotake, Miyazaki, Japan
Department of Biochemistry, Miyazaki Medical College, Kiyotake, Miyazaki, Japan; Second Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki, Japan
Second Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki, Japan
Second Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Kumamoto, Japan
The Cancer Institute, Japanese Foundation for Cancer Reseach, Toshoma-ku, Tokyo, Japan
* Corresponding author; email: kmorishi{at}post.miyazaki-med.ac.jp.
We have identified a novel gene MEL1 (MDS1/EVI1-like gene 1) encoding a zinc finger protein near the breakpoint of t(1;3)(p36;q21)-positive human acute myeloid leukemia (AML) cells. Here, we studied the structure, expression pattern, and function of MEL1 in leukemia cells. From the results of cDNA cloning, RNase protection, primer extension, in vitro transcription/translation and mammalian cell expression experiments, we have identified three transcription start sites, one in exon 1 (MEL1) and two in exon 2 (MEL1S), and two kinds of translation products, 170-kDa and 150-kDa. Notably, the 150-kDa band of MEL1 was mainly detected in the t(1;3)(p36;q21)-positive AML cells. When MEL1S or_D13MEL1 cDNA lacking the first 4 ATG sites (exons 1 to 3), was transfected into the COS7 cells, the same 150-kDa band was detected in each cDNA by immunoblot analysis and the 150-kDa band in leukemia cells showed the same proteolytic mapping. It is suggested that MEL1S in the leukemia cells is translated from the internal initiation codon ATG597 in exon 4 and is mostly lacking the amino-terminal PR domain of MEL1. By the cyclic amplification and selection of targets (CASTing) method for identifying consensus sequences, it was shown that the consensus sequences of MEL1 were included in two different consensus sequences for DNA-binding domain 1 and 2 (D1-CONS and D2-CONS) of EVI1. In reporter gene assays, MEL1S activated transcription via binding to D2-CONS, however, the fusion of MEL1 or MEL1S to GAL4 DNA-binding domain (DBD) made them GAL4 binding site-dependent transcriptional repressors, indicating their different intrinsic functions may be involved in the transcriptional activation or repression. Moreover, overexpression of MEL1S blocked granulocytic differentiation induced by G-CSF in IL-3-dependent murine myeloid L-G3 cells, while MEL1 could not block the differentiation. Thus, it is likely that overexpression of the zinc finger protein lacking the PR domain (EVI1 and MEL1S) in the leukemia cells is one of the main causative factors in the pathogenesis of myeloid leukemia.
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