AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations

Y. Yuan, L. Zhou, Toshihiro Miyamoto, H. Iwasaki, N. Harakawa, C. J. Hetherington, S. A. Burel, E. Lagasse, I. L. Weissman, Koichi Akashi, D. E. Zhang

Research output: Contribution to journalArticle

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Abstract

The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expression of AML1-ETO is under the control of the human MRP8 promoter (hMRP8-AML1-ETO). AML1-ETO is specifically expressed in myeloid cells, including common myeloid progenitors of hMRP8-AML1-ETO transgenic mice. The transgenic mice were healthy during their life spans, suggesting that AML1-ETO alone is not sufficient for leukemogenesis. However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia. Our results provide direct evidence that AML1-ETO is critical for causing myeloid leukemia, but one or more additional mutations are required for leukemogenesis. The hMRP8-AML1-ETO-transgenic mice provide an excellent model that can be used to isolate additional genetic events and to further understand the molecular pathogenesis of AML1-ETO-related leukemia.

Original languageEnglish
Pages (from-to)10398-10403
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number18
DOIs
Publication statusPublished - Aug 28 2001

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Acute Myeloid Leukemia
Transgenic Mice
Mutation
Ethylnitrosourea
Myeloid Progenitor Cells
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 8
Myeloid Leukemia
Mutagens
Myeloid Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Chromosome Aberrations
Genes
Leukemia
Transcription Factors
DNA
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • General

Cite this

AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. / Yuan, Y.; Zhou, L.; Miyamoto, Toshihiro; Iwasaki, H.; Harakawa, N.; Hetherington, C. J.; Burel, S. A.; Lagasse, E.; Weissman, I. L.; Akashi, Koichi; Zhang, D. E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 18, 28.08.2001, p. 10398-10403.

Research output: Contribution to journalArticle

Yuan, Y. ; Zhou, L. ; Miyamoto, Toshihiro ; Iwasaki, H. ; Harakawa, N. ; Hetherington, C. J. ; Burel, S. A. ; Lagasse, E. ; Weissman, I. L. ; Akashi, Koichi ; Zhang, D. E. / AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 18. pp. 10398-10403.
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