Dichotomy of AML1-ETO functions: Growth arrest versus block of differentiation

The fusion gene AML1-ETO is the product of t(8;21)(q22;q22), one of the mos t common chromosomal translocations associated with acute myeloid leukemia. To investigate the impact of AML1-ETO on hematopoiesis, tetracycline-induc ible AML1-ETO-expressing cell lines were generated using myeloid cells. AML 1-ETO is tightly and strongly induced upon tetracycline withdrawal. The pro liferation of AML1-ETO+ cells was markedly reduced, and most of the cells e ventually underwent apoptosis. RNase protection assays revealed that the am ount of Bcl-2 mRNA was decreased after AML1-ETO induction. Enforced express ion of Bcl-2 was able to significantly delay, but not completely overcome, AML1-ETO-induced apoptosis. Prior to the onset of apoptosis, we also studie d 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 a (C/EBP alpha), a key regulator of granulo cytic differentiation. These observations suggest a dichotomy in the functi ons of AML1-ETO: (i) reduction of granulocytic differentiation correlated w ith decreased expression of C/EBP alpha and (ii) growth arrest leading to a poptosis with decreased expression of CDK4, c-myc, and Bcl-2. We predict th at the preleukemic AML1-ETO+ cells must overcome AML1-ETO-induced growth ar rest and apoptosis prior to fulfilling their leukemogenic potential.