A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF–induced myeloid differentiation

• Ichiro Nishikata

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Hidenori Sasaki

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Mutsunori Iga

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Yoko Tateno

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Suzuko Imayoshi

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Norio Asou

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Takuro Nakamura

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

• Kazuhiro Morishita

  From the Department of Biochemistry and Second Department of Internal Medicine, Miyazaki Medical College, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; and The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

抄録

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. In this study, we have identified 3 transcription start sites, 1 in exon 1 and 2 in exon 2, and 2 kinds of translation products, 170 kDa (MEL1) and 150 kDa (MEL1S). Notably, the 150-kDa band of MEL1S was detected mainly in the t(1;3)(p36;q21)-positive AML cells. By immunoblot analysis and proteolytic mapping, it is suggested that the 150-kDa band of 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 2 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. Moreover, overexpression of MEL1S blocked granulocytic differentiation induced by granulocyte colony-stimulating factor (G-CSF) in interleukin-3 (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 causative factors in the pathogenesis of myeloid leukemia.

収録刊行物

• Blood

  Blood 102 (9), 3323-3332, 2003-11-01

  American Society of Hematology

キーワード

• Cell Biology
• Hematology
• Immunology
• Biochemistry

詳細情報

• CRID: 1363670319671698944
• NII論文ID: 30022496310
• DOI: 10.1182/blood-2002-12-3944
• ISSN: 15280020
• ISSN: 00064971
• Web Site: http://ashpublications.org/blood/article-pdf/102/9/3323/1692944/h82103003323.pdf
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