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Molecular and Cellular Biology, August 2002, p. 5506-5517, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5506-5517.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Hematopoietic Stem Cell Expansion and Distinct Myeloid Developmental Abnormalities in a Murine Model of the AML1-ETO Translocation

Cristina G. de Guzman,1 Alan J. Warren,2 Zheng Zhang,3 Larry Gartland,3 Paul Erickson,4 Harry Drabkin,4 Scott W. Hiebert,5 and Christopher A. Klug3*

Department of Human Genetics,1 Department of Microbiology, Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, Alabama 35294,3 MRC Laboratory of Molecular Biology, Cambridge, United Kingdom,2 University of Colorado Health Sciences Center, Denver, Colorado 80262,4 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 372325

Received 7 January 2002/ Returned for modification 1 March 2002/ Accepted 24 April 2002

The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO), is one of the most frequent cytogenetic abnormalities associated with acute myelogenous leukemia (AML). It is seen in approximately 12 to 15% of AML cases and is present in about 40% of AML cases with a French-American-British classified M2 phenotype. We have generated a murine model of the t(8;21) translocation by retroviral expression of AML1-ETO in purified hematopoietic stem cells (HSC). Animals reconstituted with AML1-ETO-expressing cells recapitulate the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21) translocation. Primitive myeloblasts were increased to approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. Accumulation of late-stage metamyelocytes was also observed in bone marrow along with an increase in immature eosinophilic myelocytes that showed abnormal basophilic granulation. HSC numbers in the bone marrow of 10-month-posttransplant animals were 29-fold greater than in transplant-matched control mice, suggesting that AML1-ETO expression overrides the normal genetic control of HSC pool size. In summary, AMLI-ETO-expressing animals recapitulate many (and perhaps all) of the developmental abnormalities seen in human patients with the t(8;21) translocation, although the animals do not develop leukemia or disseminated disease in peripheral tissues like the liver or spleen. This suggests that the principal contribution of AML1-ETO to acute myeloid leukemia is the inhibition of multiple developmental pathways.

* Corresponding author. Mailing address: University of Alabama at Birmingham, WTI 387, 1824 6th Ave. South, Birmingham, AL 35294. Phone: (205) 934-1424. Fax: (205) 934-1875. E-mail: chris.klug{at}ccc.uab.edu.

Molecular and Cellular Biology, August 2002, p. 5506-5517, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5506-5517.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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