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The AML-1 fusion gene promotes extensive self-renewal of human primary erythroid cells

Tonks, Alex ORCID:, Pearn, Lorna, Tonks, Amanda Jayne, Pearce, Laurence, Hoy, Terence George, Phillips, Sarah, Fisher, Janet, Downing, James R., Burnett, Alan Kenneth and Darley, Richard Lawrence ORCID: 2003. The AML-1 fusion gene promotes extensive self-renewal of human primary erythroid cells. Blood 101 (2) , pp. 624-632. 10.1182/blood-2002-06-1732

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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. (Blood. 2003;101:624-632)

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISSN: 1528-0020
Last Modified: 01 Jul 2024 14:19

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