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

doi:10.1128/MCB.21.16.5577-5590.2001

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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 associatedwith acute myeloid leukemia. To investigate the impact of AML1-ETOon hematopoiesis, tetracycline-inducible AML1-ETO-expressing celllines were generated using myeloid cells. AML1-ETO is tightlyand strongly induced upon tetracycline withdrawal. The proliferationof AML1-ETO⁺ cells was markedly reduced, and most of the cells eventuallyunderwent apoptosis. RNase protection assays revealed that theamount of Bcl-2 mRNA was decreased after AML1-ETO induction. Enforcedexpression of Bcl-2 was able to significantly delay, but not completelyovercome, 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/Ecells. More significantly, this change of differentiation wasassociated with the down-regulation of CCAAT/enhancer bindingprotein $alpha$ (C/EBP $alpha$ ), a key regulator of granulocytic differentiation.These observations suggest a dichotomy in the functions of AML1-ETO:(i) reduction of granulocytic differentiation correlated withdecreased expression of C/EBP $alpha$ and (ii) growth arrest leadingto 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 apoptosisprior to fulfilling their leukemogenicpotential.

^* Corresponding author. Mailing address: MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA92037. Phone: (858) 784-9581. Fax: (858) 784-9593. E-mail: dzhang{at}Scripps.edu.

Paper 13690-MEM from The Scripps ResearchInstitute.

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