The AML 1 / ETO ( MTG 8 ) and AML 1 / Evi - 1 Leukemia - Associated Chimeric Oncoproteins Accumulate PEBP

نویسندگان

  • Kozo Tanaka
  • Tomoyuki Tanaka
  • Mineo Kurokawa
  • Yoichi Imai
  • Seishi Ogawa
  • Kinuko Mitani
  • Yoshio Yazaki
  • Hisamaru Hirai
چکیده

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)2b(core binding factor [CBF]b), 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 PEBP2b(CBFb), more of the cells expressing the chimeric proteins showed the nuclear accumulation of PEBP2b(CBFb), as compared with the cells expressing wild-type AML1. We also showed that the chimeric proteins associate with PEBP2b(CBFb) more effectively than wild-type AML1. These data suggest that the chimeric proteins are able to accumulate PEBP2b(CBFb) in the nucleus more efficiently than wild-type AML1, probably because of the higher affinities of the chimeric proteins for PEBP2b(CBFb) than that of wild-type AML1. These effects of the chimeric proteins on the cellular distribution of PEBP2b(CBFb) 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. r 1998 by The American Society of Hematology.

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The AML 1 / ETO ( MTG 8 ) and AML 1 / Evi - 1 Leukemia - Associated Chimeric Oncoproteins Accumulate

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...

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تاریخ انتشار 1998