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Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development.


ABSTRACT: Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR/SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.

SUBMITTER: Yan M 

PROVIDER: S-EPMC535382 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development.

Yan Ming M   Burel Sebastien A SA   Peterson Luke F LF   Kanbe Eiki E   Iwasaki Hiromi H   Boyapati Anita A   Hines Robert R   Akashi Koichi K   Zhang Dong-Er DE  

Proceedings of the National Academy of Sciences of the United States of America 20041129 49


Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses  ...[more]

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