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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-06-1732.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 624-632
NEOPLASIA
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
From the Department of Haematology, University of Wales
College of Medicine, Cardiff, United Kingdom; and
Department of Pathology, St Jude Children's Research Hospital,
Memphis, TN.
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 leukemia, although its role in leukemogenesis 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 while AML1-ETO initially inhibited proliferation
during early (erythropoietin [EPO]-independent) erythropoiesis,
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 to 13 days (at the
EPO-dependent stage of development). Phenotypic analysis showed that
although these cells were CD13 and 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 occur. In the early stages of this expansion, addition of EPO was
able to promote both phenotypic (CD36+, CD33,
glycophorin A+) and morphologic 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 hematopoietic cells and therefore
support a causal role for t(8;21) translocations in leukemogenesis.
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