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PMID: 11526243 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 18 ·2001-08-28 ·Pages 10398-403

Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, Burel SA, Lagasse E, Weissman IL, Akashi K, Zhang DE

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.

MeSH Terms
Animals Antigens, Differentiation/genetics Base Sequence Calcium-Binding Proteins/genetics Calgranulin A Carcinogens/toxicity Chromosomes, Human, Pair 21/genetics Chromosomes, Human, Pair 8/genetics Core Binding Factor Alpha 2 Subunit DNA Primers/genetics Ethylnitrosourea/toxicity Gene Expression Hematopoiesis/genetics Humans Leukemia, Myeloid, Acute/etiology,genetics,pathology Mice Mice, Transgenic Mutation Oncogene Proteins, Fusion/genetics Promoter Regions, Genetic RUNX1 Translocation Partner 1 Protein Transcription Factors/genetics Translocation, Genetic
Chemicals
AML1-ETO fusion protein, human Antigens, Differentiation Calcium-Binding Proteins Calgranulin A Carcinogens Core Binding Factor Alpha 2 Subunit DNA Primers Oncogene Proteins, Fusion RUNX1 Translocation Partner 1 Protein Transcription Factors Ethylnitrosourea
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Yuan Y
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zhou L
Miyamoto T
Iwasaki H
Harakawa N
Hetherington C J
Burel S A
Lagasse E
Weissman I L
Akashi K
Zhang D E
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.171321298
Published
2001-08-28
Pages
10398-403
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC56972
Subset
IM
Grants
NCI NIH HHS · P01 CA072009 · United States
NCI NIH HHS · CA72009 · United States
External Links
PubMed source DOI: 10.1073/pnas.171321298 PMC Full Text View journal details
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