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Molecular and Cellular Biology, August 2001, p. 5577-5590, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5577-5590.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dichotomy of AML1-ETO Functions: Growth Arrest versus Block of Differentiation†

Sebastien A. Burel,1 Nari Harakawa,2 Liming Zhou,1 Thomas Pabst,2 Daniel G. Tenen,2 and Dong-Er Zhang1,*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,1 and Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 021152

Received 20 November 2000/Returned for modification 8 January 2001/Accepted 7 May 2001

The fusion gene AML1-ETO is the product of t(8;21)(q22;q22), one of the most common chromosomal translocations associated with acute myeloid leukemia. To investigate the impact of AML1-ETO on hematopoiesis, tetracycline-inducible AML1-ETO-expressing cell lines were generated using myeloid cells. AML1-ETO is tightly and strongly induced upon tetracycline withdrawal. The proliferation of AML1-ETO+ cells was markedly reduced, and most of the cells eventually underwent apoptosis. RNase protection assays revealed that the amount of Bcl-2 mRNA was decreased after AML1-ETO induction. Enforced expression of Bcl-2 was able to significantly delay, but not completely overcome, AML1-ETO-induced apoptosis. Prior to the onset of apoptosis, we also studied the ability of AML1-ETO to modulate differentiation. AML1-ETO expression altered granulocytic differentiation of U937T-A/E cells. More significantly, this change of differentiation was associated with the down-regulation of CCAAT/enhancer binding protein alpha  (C/EBPalpha ), a key regulator of granulocytic differentiation. These observations suggest a dichotomy in the functions of AML1-ETO: (i) reduction of granulocytic differentiation correlated with decreased expression of C/EBPalpha and (ii) growth arrest leading to apoptosis with decreased expression of CDK4, c-myc, and Bcl-2. We predict that the preleukemic AML1-ETO+ cells must overcome AML1-ETO-induced growth arrest and apoptosis prior to fulfilling their leukemogenic potential.

* Corresponding author. Mailing address: MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9581. Fax: (858) 784-9593. E-mail: dzhang{at}Scripps.edu.

dagger Paper 13690-MEM from The Scripps Research Institute.

Molecular and Cellular Biology, August 2001, p. 5577-5590, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5577-5590.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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