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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-06-1732.
Submitted June 12, 2002
Accepted August 12, 2002
The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells
Alex Tonks*, Lorna Pearn, Amanda J Tonks, Laurence Pearce, Terry Hoy, Sarah Phillips, Janet Fisher, James R Downing, Alan K Burnett, and Richard L Darley
Department of Haematology, University of Wales College of Medicine, Cardiff, United Kingdom
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: tonksa{at}cf.ac.uk.
The t(8;21) translocation which encodes the AML1-ETO fusion protein (now known as RUNX1-CBF2T1), is one of the most frequent translocations in acute myeloid leukaemia, though its role in leukaemogenesis is unclear. Here, we report that exogenous expression of AML1-ETO in human CD34+ cells severely disrupts normal erythropoiesis resulting in virtual abrogation of erythroid colony formation. In contrast, in bulk liquid culture of purified erythroid cells, we found that during early (erythropoietin-independent) erythropoiesis, though AML1-ETO initially inhibited proliferation, growth inhibition gave way to a sustained EPO-independent expansion of early erythroid cells that continued for more than 60 days, whereas control cultures became growth arrested after 10-13 days (at the EPO-dependent stage of development). Phenotypic analysis showed that while these cells were CD13-, CD34-, unlike control cultures, these cells failed to up-regulate CD36 or to down-regulate CD33 suggesting that expression of AML1-ETO suppressed the differentiation of these cells and allowed extensive self-renewal to take place. In the early stages of this expansion, addition of EPO was able to promote both phenotypic (CD36+, CD33-, glycophorin A+) and morphological differentiation of these cells, almost as effectively as in control cultures. However, with extended culture, cells expressing AML1-ETO became refractory to addition of this cytokine suggesting that a block in differentiation had been established. These data demonstrate the capacity of AML1-ETO to promote the self-renewal of human haematopoietic cells and therefore support a causal role for t(8;21) translocations in leukaemogenesis.
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