Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development
- Ming Yan*,†,
- Sebastien A. Burel*,†,
- Luke F. Peterson*,†,
- Eiki Kanbe*,
- Hiromi Iwasaki‡,
- Anita Boyapati*,
- Robert Hines*,
- Koichi Akashi‡, and
- Dong-Er Zhang*,§
- *Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and ‡Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
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Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved October 18, 2004 (received for review September 12, 2004)
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.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: dzhang{at}scripps.edu.
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↵ † M.Y., S.A.B., and L.F.P. contributed equally to the work.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: AML, acute myeloid leukemia; En, embryonic day n; HA, hemagglutinin.
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See Commentary on page 16985.
- Copyright © 2004, The National Academy of Sciences
